Yunpeng Wang

• Kvalvik, Eirik Haugland; Wang, Yunpeng; Walhovd, Kristine B; Lyngstad, Torkild Hovde & Røgeberg, Ole (2026). Beyond years of schooling: Genetic associations across educational milestones in two Norwegian cohorts. PLoS Genetics. ISSN 1553-7390. 22(9). doi: 10.1371/journal.pgen.1012310. Full text in Research Archive Show summary

  Although educational attainment is heritable, years-of-education (EduYears) measures are not designed to show how genetic associations vary across discrete educational milestones. In the Norwegian Mother, Father and Child Cohort Study (MoBa; N = 120,527) and the Norwegian Twin Registry (N = 8,910), we combined genome-wide association studies (GWAS), polygenic indices (PGIs), and twin models to characterize genetic associations with high-school completion and bachelor’s, master’s, and doctoral attainment. In transition-specific analyses conditional on prior attainment, observed-scale common-variant heritability (h 2 SNP ) and PGI discrimination followed an inverse-U pattern, peaking for progression from high-school completion to attainment of at least a bachelor’s degree (HS → BSc + ; h 2 SNP  ≈ 0.14; R 2 Tjur  ≈ 0.05) and declining at postgraduate transitions. Genetic correlations (r g ) with large-scale GWAS of EduYears (EA4) and intelligence were high at earlier transitions but lower at later ones (for EA4, r g  ≈ 0.92 at HS → BSc+ and ≈ 0.38 at MSc → PhD). In cumulative analyses of attained status in the full cohort, the point-estimate gap between twin- and SNP-based heritability narrowed from ≈ 0.38 at high-school completion to ≈ 0.11 at PhD, while genetic overlap was lower for distant than adjacent milestones (r g  ≈ 0.71 for high-school completion versus PhD and ≈ 0.92 for adjacent milestones). Sensitivity analyses using an alternative intelligence GWAS and additional PGIs showed similar transition-specific trajectories. At the doctoral transition, estimates were obtained among individuals who had attained at least a master’s degree, so attenuation there must be interpreted in light of selection and range restriction. Because EduYears converts distinct credentials and progression steps into a single numerical scale, estimates expressed per additional year should not be interpreted as though one year has the same meaning across the educational sequence. Milestone-preserving analyses make that hidden structure visible and sharpen the interpretation of education GWAS and PGIs.

• Kraft, Brage; MacSweeney, Niamh Anne; Page, Christian Magnus; Lyle, Robert; Tsotsi, Stella & Ulset, Vidar Sandsaunet [Show all 12 contributors for this article] (2026). The effect of prenatal maternal stress on adolescent internalizing symptoms and the genetic moderation of executive functioning and prefrontal cortex. Psychological Medicine. ISSN 0033-2917. 56. doi: 10.1017/S0033291726105431. Full text in Research Archive Show summary

  Background: Prenatal maternal stress is a known risk factor for later emotional problems, yet not all exposed offspring develop psychopathology. Executive functioning and prefrontal cortex structure and activity may buffer these effects, but it remains unclear whether genetic predis positions in these domains moderate associations with adolescent internalizing symptoms. Methods: We examined 3,111 adolescents (1,881 females, 1,230 males). Prenatal stress was measured via a cumulative index across four domains. Internalizing symptoms were self reported at ages 14 and 16. Genetic predisposition for executive functioning was indexed using a polygenic score (PGS) derived from adult samples, applied here to estimate genetic predis position for executive functioning in adolescence. We also estimated a prefrontal cortex PGS based on cortical thickness and activation in six prefrontal regions, with a composite index derived from the first principal axis summarizing these measures. Results: Higher prenatal stress was significantly associated with more internalizing symptoms in adolescence. Female sex and maternal genetic risk for internalizing symptoms were also associated with higher symptom levels. Neither genetic disposition for executive functioning nor prefrontal cortex moderated this association overall. However, a weak interaction emerged at age 16, indicating that a genetic disposition for higher executive functioning was associated with greater internalizing symptoms under high stress exposure. Conclusions: Prenatal maternal stress predicted increased adolescent internalizing symptoms, with limited evidence for moderation by genetic predisposition for executive functioning. Higher genetic potential for executive functioning may confer increased sensitivity to early stress under certain developmental conditions.

• Walhovd, Kristine B; Bråthen, Anne Cecilie Sjøli; Øverbye, Knut Eiliv Ødegård; Kransberg, Jonas Moe; Sørensen, Øystein & Garrido, Pablo F. [Show all 19 contributors for this article] (2026). Feature-specific environmental contributions to human cortical architecture revealed by twin brainprints. Communications Biology. doi: 10.1038/s42003-026-10707-w. Full text in Research Archive Show summary

  Abstract How environmental variation shapes the human cerebral cortex remains incompletely understood. Here we compare cortical brainprints – individual profiles of regional cortical morphology – in 210 twins (age 16-78 years) to distinguish prenatal, adult naturalistic and experimentally induced environmental variation from genetic contributions. Monozygotic twins showed higher brainprint similarity than dizygotic twins, consistent with genetic effects. Lasting influences of early environment were evident in lower brainprint similarity in monozygotic twin-pairs with greater birthweight discordances, driven by surface area across the cortical ribbon. In contrast, within-pair differences in adult weight and lifestyle had minimal influence. Still, a 10-week virtual-reality navigation intervention revealed training-induced changes in the gray-white interface, with curvature and area changes supported by microstructural reconfigurations. Relative brainprint similarity increased in monozygotic but diverged in dizygotic pairs following training. These findings show that distinct environmental influences acting at prenatal and adult stages are reflected in different features of the human cerebral cortex.

• Xu, Haotian; Wen, Lu; Cao, Shixin; Huang, Yu; Zhao, Xiaoli & Zeng, Xiaopeng [Show all 17 contributors for this article] (2026). Natural killer cell reduction and dysfunction define a pathogenic and diagnostic axis in neuromyelitis optica spectrum disorder. Journal of Neuroinflammation. 23(1). doi: 10.1186/s12974-026-03710-9. Full text in Research Archive Show summary

  Neuromyelitis optica spectrum disorder (NMOSD) is a severe relapsing autoimmune disease of the central nervous system, where early diagnosis and monitoring are essential to prevent long-term disability. The cell-based assay recommended for aquaporin-4 immunoglobulin G (AQP4-IgG) serology offers well-established diagnostic accuracy, however, it is costly, time-consuming and not universally accessible in some hospitals. Here, we identify peripheral natural killer (NK) cell reduction as a readily accessible and quantifiable complementary diagnostic biomarker for NMOSD. Across two independent cohorts, NK cell was significantly reduced in NMOSD patients compared to healthy controls and other central nervous system (CNS) demyelinating disorders including multiple sclerosis (MS), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and autoimmune encephalitis (AE). Using single-cell RNA sequencing, we demonstrate that NK cells exhibit distinct transcriptional dysfunctions involving cytokine production, immune regulation, and cellular migration. Further, cell-cell interaction analysis revealed impaired interferon-gamma (IFN-γ) signaling between NK and B cells, likely contributing to pathological B cell activation. Longitudinal analyses showed persistent NK cell reduction during active and post-treatment phases, with partial recovery in remission, supporting their use in disease monitoring. Finally, weighted gene co-expression network analysis identified NK gene modules strongly associated with disease severity and enriched in proinflammatory and B cell-activating pathways. Together, our findings position NK cell reduction and dysfunction as central features of NMOSD immunopathology and establish NK cell proportion and gene activity as potential biomarkers for diagnosis, differential diagnosis, and disease progression.

• Wu, Jing; Zhou, Xingyu; Luo, Tiandong; Wang, Xin; Zuo, Hongzhou & Yang, Ruijing [Show all 21 contributors for this article] (2026). Microbiota-Driven microglia reprogramming reverses depressive-like behaviors through Peripheral-to-Central immune crosstalk. Molecular Psychiatry. ISSN 1359-4184. doi: 10.1038/s41380-026-03545-z. Full text in Research Archive
• Shen, Jie; Valentim, Wander; Friligkou, Eleni; Overstreet, Cassie; Choi, Karmel W. & Koller, Dora [Show all 245 contributors for this article] (2025). Shared genetic architecture of posttraumatic stress disorder with cardiovascular imaging, risk, and diagnoses. Nature Communications. 16(1). doi: 10.1038/s41467-025-60487-w. Full text in Research Archive Show summary

  Patients with post-traumatic stress disorder face increased cardiovascular risk. This study examines shared genetic regions between post-traumatic stress disorder and 246 cardiovascular conditions across electronic health records, 82 cardiac imaging, and health behaviors defined by Life’s Essential 8. Post-traumatic stress disorder is genetically correlated with cardiovascular diagnoses in 33 regions, imaging traits in 4 regions, and health behaviors in 44 regions. Potentially shared causal variants between post-traumatic stress disorder and 17 cardiovascular conditions were observed in 11 regions. Subsequent observational analysis in AllofUS cohort showed post-traumatic stress disorder is associated with 13 diagnoses even after accounting for socioeconomic factors and depression. Genetically regulated proteome expression in brain and blood tissues identified 33 blood and 122 brain genes shared between the two conditions, revealing neuronal, immune, metabolic, and calcium-related mechanisms, with several genes as targets for existing drugs. These findings exhibit shared risk loci and genes are involved in tissue-specific mechanisms.

• Kvalvik, Eirik Haugland; Røgeberg, Ole; Wang, Yunpeng; Lyngstad, Torkild Hovde & Walhovd, Kristine B (2025). Beyond years of schooling: Shifting genetic influences across educational milestones in two Norwegian cohorts | bioRxiv. bioRxiv. ISSN 2692-8205. doi: 10.1101/2025.10.08.680992. Full text in Research Archive Show summary

  bioRxiv - the preprint server for biology, operated by Cold Spring Harbor Laboratory, a research and educational institution

• Iakunchykova, Olena; Schirmer, Henrik; Roe, James Michael; Sørensen, Øystein; Wilsgaard, Tom & Hopstock, Laila Arnesdatter [Show all 10 contributors for this article] (2025). Longitudinal and concurrent C-reactive protein and diet associations with cognitive function in the population-based Tromsø study. Journal of Alzheimer's Disease. ISSN 1387-2877. 104(2), p. 403–413. doi: 10.1177/13872877251317624. Full text in Research Archive
• Liang, Yuanyuan; Ma, Dongrui; Li, Mengjie; Wang, Zhiyun; Hao, Chenwei & Sun, Yuemeng [Show all 16 contributors for this article] (2025). Exome sequencing identifies novel genes associated with cerebellar volume and microstructure. Communications Biology. 8(1). doi: 10.1038/s42003-025-07797-3. Full text in Research Archive Show summary

  Proteins encoded by exons are critical for cellular functions, and mutations in these genes often result in significant phenotypic effects. The cerebellum is linked to various heritable human disease phenotypes, yet genome-wide association studies have struggled to capture the effects of rare variants on cerebellar traits. This study conducts a large-scale exome association analysis using data from approximately 35,000 UK Biobank participants, examining seven cerebellar traits, including total cerebellar volume and white matter microstructure. We identify 90 genes associated with cerebellar traits, 60 of which were previously unreported in genome-wide association studies. Notable findings include the discovery of genes like PRKRA and TTK, as well as RASGRP3, linked to cerebellar volume and white matter microstructure. Gene enrichment analysis reveals associations with non-coding RNA processing, cognitive function, neurodegenerative diseases, and mental disorders, suggesting shared biological mechanisms between cerebellar phenotypes and neuropsychiatric diseases.

• Walhovd, Kristine B; Krogsrud, Stine Kleppe; Amlien, Inge; Sørensen, Øystein; Wang, Yunpeng & Bråthen, Anne Cecilie Sjøli [Show all 14 contributors for this article] (2024). Fetal influence on the human brain through the lifespan. eLIFE. 12. doi: 10.7554/eLife.86812. Full text in Research Archive
• Roe, James Michael; Vidal-Piñeiro, Didac; Sørensen, Øystein; Grydeland, Håkon; Leonardsen, Esten Høyland & Iakunchykova, Olena [Show all 35 contributors for this article] (2024). Brain change trajectories in healthy adults correlate with Alzheimer’s related genetic variation and memory decline across life. Nature Communications. 15(1). doi: 10.1038/s41467-024-53548-z. Full text in Research Archive Show summary

  Throughout adulthood and ageing our brains undergo structural loss in an average pattern resembling faster atrophy in Alzheimer’s disease (AD). Using a longitudinal adult lifespan sample (aged 30-89; 2–7 timepoints) and four polygenic scores for AD, we show that change in AD-sensitive brain features correlates with genetic AD-risk and memory decline in healthy adults. We first show genetic risk links with more brain loss than expected for age in early Braak regions, and find this extends beyond APOE genotype. Next, we run machine learning on AD-control data from the Alzheimer’s Disease Neuroimaging Initiative using brain change trajectories conditioned on age, to identify AD-sensitive features and model their change in healthy adults. Genetic AD-risk linked with multivariate change across many AD-sensitive features, and we show most individuals over age ~50 are on an accelerated trajectory of brain loss in AD-sensitive regions. Finally, high genetic risk adults with elevated brain change showed more memory decline through adulthood, compared to high genetic risk adults with less brain change. Our findings suggest quantitative AD risk factors are detectable in healthy individuals, via a shared pattern of ageing- and AD-related neurodegeneration that occurs along a continuum and tracks memory decline through adulthood.

• Reppe, Sjur; Gundersen, Sveinung; Sandve, Geir Kjetil Ferkingstad; Wang, Yunpeng; Andreassen, Ole A. & Medina-Gomez, Carolina [Show all 10 contributors for this article] (2024). Identification of Transcripts with Shared Roles in the Pathogenesis of Postmenopausal Osteoporosis and Cardiovascular Disease. International Journal of Molecular Sciences. ISSN 1661-6596. 25(10). doi: 10.3390/ijms25105554. Full text in Research Archive Show summary

  Epidemiological evidence suggests existing comorbidity between postmenopausal osteoporosis (OP) and cardiovascular disease (CVD), but identification of possible shared genes is lacking. The skeletal global transcriptomes were analyzed in trans-iliac bone biopsies (n=84) from clinically well-characterized postmenopausal women (50 to 86 years) using microchips and RNA sequencing. Thousand transcripts highly correlated with areal bone mineral density (aBMD) were further analyzed using bioinformatics, and common genes overlapping with CVD and their biological mechanisms, pathways and functions were identified. Fifty genes (45 mRNAs, 5 miRNAs) were discovered with established roles in oxidative stress, inflammatory response, endothelial function, fibrosis, dyslipidemia and osteoblastogenesis/calcification. These pleiotropic genes with possible CVD comorbidity functions were also present in transcriptomes of microvascular endothelial cells and cardiomyocytes and differentially expressed between healthy and osteoporotic women with fragility fractures. The results were supported by a genetic pleiotropy-informed conditional False Discovery Rate approach identifying overlap in single nucleotide polymorphisms (SNPs) within several genes encoding the aBMD and CVD associated transcripts.The study provides transcriptional and genomic evidence for genes of importance for both BMD regulation and CVD risk in a large collection of postmenopausal bone biopsies. Most of the transcripts identified in the CVD risk categories have no previously recognized roles in OP pathogenesis and provide novel avenues for exploring the mechanistic basis for the biological association between CVD and OP.

• Zhang, Liyuan; Yuan, Xiuxia; Li, Xue; Xiaoyun, Zhang; Hu, Shaohua & Andreassen, Ole A. [Show all 8 contributors for this article] (2024). Gut microbial diversity moderates polygenic risk of schizophrenia. Frontiers in Psychiatry. 15. doi: 10.3389/fpsyt.2024.1275719. Full text in Research Archive Show summary

  Background: Schizophrenia (SCZ) is a heritable disorder with a polygenic architecture, and the gut microbiota seems to be involved in its development and outcome. In this study, we investigate the interplay between genetic risk and gut microbial markers. Methods: We included 159 first-episode, drug-naïve SCZ patients and 86 healthy controls. The microbial composition of feces was characterized using the 16S rRNA sequencing platform, and five microbial α-diversity indices were estimated [Shannon, Simpson, Chao1, the Abundance-based Eoverage Estimator (ACE), and a phylogenetic diversity-based estimate (PD)]. Polygenic risk scores (PRS) for SCZ were constructed using data from large-scale genome-wide association studies. Effects of microbial α-diversity, microbial abundance, and PRS on SCZ were evaluated via generalized linear models. Results: We confirmed that PRS was associated with SCZ (OR = 2.08, p = 1.22×10−5) and that scores on the Shannon (OR = 0.29, p = 1.15×10−8) and Simpson (OR = 0.29, p = 1.25×10−8) indices were inversely associated with SCZ risk. We found significant interactions (p < 0.05) between PRS and α-diversity indices (Shannon, Simpson, and PD), with the effects of PRS being larger in those exhibiting higher diversity compared to those with lower diversity. Moreover, the PRS effects were larger in individuals with a high abundance of the genera Romboutsia, Streptococcus, and Anaerostipes than in those with low abundance (p < 0.05). All three of these genera showed protective effects against SCZ. Conclusion: The current findings suggest an interplay between the gut microbiota and polygenic risk of SCZ that warrants replication in independent samples. Experimental studies are needed to determine the underpinning mechanisms.

• He, Qiang; Wang, Wenjing; Xu, Dingkang; Xiong, Yang; Tao, Chuanyuan & You, Chao [Show all 185 contributors for this article] (2024). Potential causal association between gut microbiome and posttraumatic stress disorder. Translational Psychiatry. 14(1). doi: 10.1038/s41398-024-02765-7. Full text in Research Archive Show summary

  Background The causal effects of gut microbiome and the development of posttraumatic stress disorder (PTSD) are still unknown. This study aimed to clarify their potential causal association using mendelian randomization (MR). Methods The summary-level statistics for gut microbiome were retrieved from a genome-wide association study (GWAS) of the MiBioGen consortium. As to PTSD, the Freeze 2 datasets were originated from the Psychiatric Genomics Consortium Posttraumatic Stress Disorder Working Group (PGC-PTSD), and the replicated datasets were obtained from FinnGen consortium. Single nucleotide polymorphisms meeting MR assumptions were selected as instrumental variables. The inverse variance weighting (IVW) method was employed as the main approach, supplemented by sensitivity analyses to evaluate potential pleiotropy and heterogeneity and ensure the robustness of the MR results. We also performed reverse MR analyses to explore PTSD’s causal effects on the relative abundances of specific features of the gut microbiome. Results In Freeze 2 datasets from PGC-PTSD, eight bacterial traits revealed a potential causal association between gut microbiome and PTSD (IVW, all P < 0.05). In addition, Genus.Dorea and genus.Sellimonas were replicated in FinnGen datasets, in which eight bacterial traits revealed a potential causal association between gut microbiome and the occurrence of PTSD. The heterogeneity and pleiotropy analyses further supported the robustness of the IVW findings, providing additional evidence for their reliability. Conclusion Our study provides the potential causal impact of gut microbiomes on the development of PTSD, shedding new light on the understanding of the dysfunctional gut-brain axis in this disorder. Our findings present novel evidence and call for investigations to confirm the association between their links, as well as to illuminate the underlying mechanisms.

• Iakunchykova, Olena; Leonardsen, Esten Høyland & Wang, Yunpeng (2024). Genetic evidence for causal effects of immune dysfunction in psychiatric disorders: where are we? Translational Psychiatry. 14(1), p. 1–11. doi: 10.1038/s41398-024-02778-2. Full text in Research Archive
• Nievergelt, Caroline M.; Maihofer, Adam X.; Atkinson, Elizabeth G.; Chen, Chia-Yen; Choi, Karmel W. & Coleman, Jonathan R. I. [Show all 235 contributors for this article] (2024). Genome-wide association analyses identify 95 risk loci and provide insights into the neurobiology of post-traumatic stress disorder. Nature Genetics. ISSN 1061-4036. 56, p. 792–808. doi: 10.1038/s41588-024-01707-9. Full text in Research Archive Show summary

  Post-traumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 new). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (for example, GRIA1, GRM8 and CACNA1E), developmental, axon guidance and transcription factors (for example, FOXP2, EFNA5 and DCC), synaptic structure and function genes (for example, PCLO, NCAM1 and PDE4B) and endocrine or immune regulators (for example, ESR1, TRAF3 and TANK). Additional top genes influence stress, immune, fear and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation.

• Iakunchykova, Olena; Pan, Mengyu; Amlien, Inge; Roe, James Michael; Walhovd, Kristine B & Fjell, Anders Martin [Show all 9 contributors for this article] (2024). Genetic evidence for the causal effects of C–reactive protein on self-reported habitual sleep duration. Brain, Behavior, and Immunity - Health (BBI - Health). 37. doi: 10.1016/j.bbih.2024.100754. Full text in Research Archive
• Leonardsen, Esten Høyland; Persson, Karin Ester Torun; Grødem, Edvard Olaf Sætersdal; Dinsdale, Nicola; SCHELLHORN, TILL & Roe, James Michael [Show all 16 contributors for this article] (2024). Constructing personalized characterizations of structural brain aberrations in patients with dementia using explainable artificial intelligence. npj Digital Medicine. 7(1). doi: 10.1038/s41746-024-01123-7. Full text in Research Archive Show summary

  Deep learning approaches for clinical predictions based on magnetic resonance imaging data have shown great promise as a translational technology for diagnosis and prognosis in neurological disorders, but its clinical impact has been limited. This is partially attributed to the opaqueness of deep learning models, causing insufficient understanding of what underlies their decisions. To overcome this, we trained convolutional neural networks on structural brain scans to differentiate dementia patients from healthy controls, and applied layerwise relevance propagation to procure individual-level explanations of the model predictions. Through extensive validations we demonstrate that deviations recognized by the model corroborate existing knowledge of structural brain aberrations in dementia. By employing the explainable dementia classifier in a longitudinal dataset of patients with mild cognitive impairment, we show that the spatially rich explanations complement the model prediction when forecasting transition to dementia and help characterize the biological manifestation of disease in the individual brain. Overall, our work exemplifies the clinical potential of explainable artificial intelligence in precision medicine.

• Pan, Mengyu; Roe, James Michael; Nudel, Ron; Schork, Andrew J.; Iakunchykova, Olena & Fjell, Anders Martin [Show all 11 contributors for this article] (2023). Circulating S100B levels at birth and risk of six major neuropsychiatric or neurological disorders: a two-sample Mendelian Randomization Study. Translational Psychiatry. 13(1). doi: 10.1038/s41398-023-02478-3. Full text in Research Archive
• Iakunchykova, Olena; Schirmer, Henrik; Vangberg, Torgil Riise; Wang, Yunpeng; Benavente, Ernest D. & Es, René van [Show all 12 contributors for this article] (2023). Machine-learning-derived heart and brain age are independently associated with cognition. European Journal of Neurology. ISSN 1351-5101. 30(9), p. 2611–2619. doi: 10.1111/ene.15902. Full text in Research Archive Show summary

  Background and purpose - A heart age biomarker has been developed using deep neural networks applied to electrocardiograms. Whether this biomarker is associated with cognitive function was investigated.<p> <p>Methods - Using 12-lead electrocardiograms, heart age was estimated for a population-based sample (N = 7779, age 40–85 years, 45.3% men). Associations between heart delta age (HDA) and cognitive test scores were studied adjusted for cardiovascular risk factors. In addition, the relationship between HDA, brain delta age (BDA) and cognitive test scores was investigated in mediation analysis.<p> <p>Results - Significant associations between HDA and the Word test, Digit Symbol Coding Test and tapping test scores were found. HDA was correlated with BDA (Pearson's r = 0.12, p = 0.0001). Moreover, 13% (95% confidence interval 3–36) of the HDA effect on the tapping test score was mediated through BDA.<p> <p>Discussion - Heart delta age, representing the cumulative effects of life-long exposures, was associated with brain age. HDA was associated with cognitive function that was minimally explained through BDA.

• Sun, Jiangming; Borné, Yan; Edsfeldt, Andreas; Wang, Yunpeng; Pan, Mengyu & Melander, Olle [Show all 8 contributors for this article] (2023). Genetic Susceptibility to Mood Disorders and Risk of Stroke: A Polygenic Risk Score and Mendelian Randomization Study. Stroke. ISSN 0039-2499. 54(5), p. 1340–1346. doi: 10.1161/STROKEAHA.122.041026. Full text in Research Archive
• Leonardsen, Esten Høyland; Vidal-Piñeiro, Didac; Roe, James Michael; Frei, Oleksandr; Shadrin, Alexey & Iakunchykova, Olena [Show all 14 contributors for this article] (2023). Genetic architecture of brain age and its casual relations with brain and mental disorders. Molecular Psychiatry. ISSN 1359-4184. doi: 10.1038/s41380-023-02087-y. Full text in Research Archive Show summary

  Abstract The difference between chronological age and the apparent age of the brain estimated from brain imaging data—the brain age gap (BAG)—is widely considered a general indicator of brain health. Converging evidence supports that BAG is sensitive to an array of genetic and nongenetic traits and diseases, yet few studies have examined the genetic architecture and its corresponding causal relationships with common brain disorders. Here, we estimate BAG using state-of-the-art neural networks trained on brain scans from 53,542 individuals (age range 3–95 years). A genome-wide association analysis across 28,104 individuals (40–84 years) from the UK Biobank revealed eight independent genomic regions significantly associated with BAG ( p  &lt; 5 × 10 −8 ) implicating neurological, metabolic, and immunological pathways – among which seven are novel. No significant genetic correlations or causal relationships with BAG were found for Parkinson’s disease, major depressive disorder, or schizophrenia, but two-sample Mendelian randomization indicated a causal influence of AD ( p  = 7.9 × 10 −4 ) and bipolar disorder ( p  = 1.35 × 10 −2 ) on BAG. These results emphasize the polygenic architecture of brain age and provide insights into the causal relationship between selected neurological and neuropsychiatric disorders and BAG.

• Fjell, Anders Martin; Sørensen, Øystein; Wang, Yunpeng; Amlien, Inge; Baaré, William F. C. & Bartrés-Faz, David [Show all 24 contributors for this article] (2023). No phenotypic or genotypic evidence for a link between sleep duration and brain atrophy. Nature Human Behaviour. 7, p. 2008–2022. doi: 10.1038/s41562-023-01707-5. Full text in Research Archive Show summary

  Abstract Short sleep is held to cause poorer brain health, but is short sleep associated with higher rates of brain structural decline? Analysing 8,153 longitudinal MRIs from 3,893 healthy adults, we found no evidence for an association between sleep duration and brain atrophy. In contrast, cross-sectional analyses (51,295 observations) showed inverse U-shaped relationships, where a duration of 6.5 (95% confidence interval, (5.7, 7.3)) hours was associated with the thickest cortex and largest volumes relative to intracranial volume. This fits converging evidence from research on mortality, health and cognition that points to roughly seven hours being associated with good health. Genome-wide association analyses suggested that genes associated with longer sleep for below-average sleepers were linked to shorter sleep for above-average sleepers. Mendelian randomization did not yield evidence for causal impacts of sleep on brain structure. The combined results challenge the notion that habitual short sleep causes brain atrophy, suggesting that normal brains promote adequate sleep duration—which is shorter than current recommendations.

• Roe, James Michael; Vidal-Piñeiro, Didac; Amlien, Inge; Pan, Mengyu; Sneve, Markus Handal & Schotten, Michel Thiebaut de [Show all 14 contributors for this article] (2023). Tracing the development and lifespan change of population-level structural asymmetry in the cerebral cortex. eLIFE. 12, p. 1–32. doi: 10.7554/eLife.84685. Full text in Research Archive
• Fjell, Anders Martin; Sørensen, Øystein; Wang, Yunpeng; Amlien, Inge; Baaré, William F C & Bartrés-Faz, David [Show all 21 contributors for this article] (2023). Is Short Sleep Bad for the Brain? Brain Structure and Cognitive Function in Short Sleepers. Journal of Neuroscience. ISSN 0270-6474. 43(28), p. 5241–5250. doi: 10.1523/JNEUROSCI.2330-22.2023. Full text in Research Archive Show summary

  Many sleep less than recommended without experiencing daytime sleepiness. According to prevailing views, short sleep increases risk of lower brain health and cognitive function. Chronic mild sleep deprivation could cause undetected sleep debt, negatively affecting cognitive function and brain health. However, it is possible that some have less sleep need and are more resistant to negative effects of sleep loss. We investigated this using a cross-sectional and longitudinal sample of 47,029 participants of both sexes (20–89 years) from the Lifebrain consortium, Human Connectome project (HCP) and UK Biobank (UKB), with measures of self-reported sleep, including 51,295 MRIs of the brain and cognitive tests. A total of 740 participants who reported to sleep &lt;6 h did not experience daytime sleepiness or sleep problems/disturbances interfering with falling or staying asleep. These short sleepers showed significantly larger regional brain volumes than both short sleepers with daytime sleepiness and sleep problems ( n = 1742) and participants sleeping the recommended 7–8 h ( n = 3886). However, both groups of short sleepers showed slightly lower general cognitive function (GCA), 0.16 and 0.19 SDs, respectively. Analyses using accelerometer-estimated sleep duration confirmed the findings, and the associations remained after controlling for body mass index, depression symptoms, income, and education. The results suggest that some people can cope with less sleep without obvious negative associations with brain morphometry and that sleepiness and sleep problems may be more related to brain structural differences than duration. However, the slightly lower performance on tests of general cognitive abilities warrants closer examination in natural settings. SIGNIFICANCE STATEMENT Short habitual sleep is prevalent, with unknown consequences for brain health and cognitive performance. Here, we show that daytime sleepiness and sleep problems are more strongly related to regional brain volumes than sleep duration. However, participants sleeping ≤6 h had slightly lower scores on tests of general cognitive function (GCA). This indicates that sleep need is individual and that sleep duration per se is very weakly if at all related brain health, while daytime sleepiness and sleep problems may show somewhat stronger associations. The association between habitual short sleep and lower scores on tests of general cognitive abilities must be further scrutinized in natural settings.

• Hemager, Nicoline; Christiani, Camilla Jerlang; Thorup, Anne Amalie Elgaard; Spang, Katrine Søborg; Ellersgaard, Ditte & Burton, Birgitte Klee [Show all 14 contributors for this article] (2022). Neurocognitive heterogeneity in 7-year-old children at familial high risk of schizophrenia or bipolar disorder: The Danish high risk and resilience study - VIA 7. Journal of Affective Disorders. ISSN 0165-0327. 302, p. 214–223. doi: 10.1016/j.jad.2022.01.096. Full text in Research Archive
• Allesøe, Rosa Lundbye; Nudel, Ron; Thompson, Wesley K.; Wang, Yunpeng; Nordentoft, Merete & Børglum, Anders D [Show all 10 contributors for this article] (2022). Deep learning-based integration of genetics with registry data for stratification of schizophrenia and depression. Science Advances. 8(26). doi: 10.1126/sciadv.abi7293. Full text in Research Archive Show summary

  Currently, psychiatric diagnoses are, in contrast to most other medical fields, based on subjective symptoms and observable signs and call for new and improved diagnostics to provide the most optimal care. On the basis of a deep learning approach, we performed unsupervised patient stratification of 19,636 patients with depression [major depressive disorder (MDD)] and/or schizophrenia (SCZ) and 22,467 population controls from the iPSYCH2012 case cohort. We integrated data of disorder severity, history of mental disorders and disease comorbidities, genetics, and medical birth data. From this, we stratified the individuals in six and seven unique clusters for MDD and SCZ, respectively. When censoring data until diagnosis, we could predict MDD clusters with areas under the curve (AUCs) of 0.54 to 0.80 and SCZ clusters with AUCs of 0.71 to 0.86. Overall cases and controls could be predicted with an AUC of 0.81, illustrating the utility of data-driven subgrouping in psychiatry.

• Jefsen, Oskar Hougaard; Nudel, Ron; Wang, Yunpeng; Bybjerg-Grauholm, Jonas; Hemager, Nicoline & Christiani, Camilla A J [Show all 17 contributors for this article] (2022). Genetic assortative mating for schizophrenia and bipolar disorder. European psychiatry. ISSN 0924-9338. 65(1). doi: 10.1192/j.eurpsy.2022.2304. Full text in Research Archive
• Cheng, Weiqiu; Meer, Dennis van der; Parker, Nadine; Hindley, Guy Frederick Lanyon; O'Connell, Kevin Sean & Wang, Yunpeng [Show all 20 contributors for this article] (2022). Shared genetic architecture between schizophrenia and subcortical brain volumes implicates early neurodevelopmental processes and brain development in childhood. Molecular Psychiatry. ISSN 1359-4184. doi: 10.1038/s41380-022-01751-z. Full text in Research Archive Show summary

  Patients with schizophrenia have consistently shown brain volumetric abnormalities, implicating both etiological and pathological processes. However, the genetic relationship between schizophrenia and brain volumetric abnormalities remains poorly understood. Here, we applied novel statistical genetic approaches (MiXeR and conjunctional false discovery rate analysis) to investigate genetic overlap with mixed effect directions using independent genome-wide association studies of schizophrenia (n = 130,644) and brain volumetric phenotypes, including subcortical brain and intracranial volumes (n = 33,735). We found brain volumetric phenotypes share substantial genetic variants (74–96%) with schizophrenia, and observed 107 distinct shared loci with sign consistency in independent samples. Genes mapped by shared loci revealed (1) significant enrichment in neurodevelopmental biological processes, (2) three co-expression clusters with peak expression at the prenatal stage, and (3) genetically imputed thalamic expression of CRHR1 and ARL17A was associated with the thalamic volume as early as in childhood. Together, our findings provide evidence of shared genetic architecture between schizophrenia and brain volumetric phenotypes and suggest that altered early neurodevelopmental processes and brain development in childhood may be involved in schizophrenia development.

• Walhovd, Kristine B; Nyberg, Lars; Lindenberger, Ulman; Amlien, Inge; Sørensen, Øystein & Wang, Yunpeng [Show all 20 contributors for this article] (2022). Brain aging differs with cognitive ability regardless of education. Scientific Reports. 12(1). doi: 10.1038/s41598-022-17727-6. Full text in Research Archive
• Hu, Maolin; Zong, Xiaofen; Sweeney, John A.; Bishop, Jeffrey R; Liao, Yanhui & Giase, Gina [Show all 15 contributors for this article] (2022). Risperidone-induced changes in DNA methylation in peripheral blood from first-episode schizophrenia patients parallel changes in neuroimaging and cognitive phenotypes. Psychiatry Research. ISSN 0165-1781. 317. doi: 10.1016/j.psychres.2022.114789. Full text in Research Archive Show summary

  Background Second generation antipsychotics such as risperidone are first-line pharmacotherapy treatment choices for schizophrenia. However, our ability to reliably predict and monitor treatment reaction is impeded by the lack of relevant biomarkers. As a biomarker for the susceptibility of schizophrenia and clozapine treatment response, DNA methylation (DNAm) has been studied, but the impact of antipsychotics on DNAm has not been explored in drug-naïve patients. Objective The aim of the present study was to examine changes of DNAm after short-term antipsychotic therapy in first-episode drug-naïve schizophrenia (FES) to identify the beneficial and adverse effect of risperidone on DNAm and their relation to treatment outcome. Methods Thirty-eight never treated schizophrenia patients and 38 demographically matched individuals (healthy controls) were assessed at baseline and at 8-week follow-up with symptom ratings, and cognitive and functional imaging procedures, at which time a blood draw for DNAm studies was performed. During the 8-week period, patients received treatment with risperidone monotherapy. An independent data set was used as replication. Results We identified brain related pathways enriched in 4,888 FES-associated CpG sites relative to controls. Risperidone administration in patients altered DNAm in 5,979 CpG sites relative to baseline. Significant group differences in DNAm at follow-up were seen in FES patients at 6,760 CpG sites versus healthy controls. Through comparison of effect size, we found 87.54% out of the risperidone-associated changes in DNAm showed possible beneficial effect, while only 12.46% showed potential adverse effect. There were 580 DNAm sites in which changes shifted methylation levels to be indistinguishable from controls after risperidone treatment. The DNAm changes of some sites that normalized after treatment were correlated with treatment-related changes in symptom severity, spontaneous neurophysiological activity, and cognition. We replicated our results in an independent data set. Conclusion The normalizing effect of risperidone monotherapy on gene DNAm, and its correlation with clinically relevant phenotypes, indicates that risperidone therapy is associated with DNAm changes that are related to changes in brain physiology, cognition and symptom severity.

• Krantz, Mette Falkenberg; Ellersgaard, Ditte; Andersen, Klaus Kaae; Hemager, Nicoline; Christiani, Camilla & Spang, Katrine Søborg [Show all 23 contributors for this article] (2022). Accumulation of Disadvantages Across Multiple Domains Amongst Subgroups of Children of Parents with Schizophrenia or Bipolar Disorder: Clustering Data from the Danish High Risk and Resilience Study VIA 7. Schizophrenia Bulletin Open. 3(1). doi: 10.1093/schizbullopen/sgac010. Full text in Research Archive Show summary

  Objective Children with familial high-risk of schizophrenia (FHR-SZ) or bipolar disorder (FHR-BP) are frequently affected in a range of domains known to be precursors of severe mental illness. No previous studies have gathered known precursors to examine whether they distribute evenly across familial high risk (FHR) children or if they cluster among a smaller group. Since such examination holds the potential to identify high and low risk of severe mental illness groups, we aimed to cluster FHR and control children affected to various degrees. Method In The Danish High Risk and Resilience Study VIA 7, a clinical cohort study, 514 7-year-old children with FHR-SZ or FHR-BP and matched controls were assessed in domains of motor function, neurocognition, emotional control, behavior, social cognition, self-perception, language, psychotic experiences, and psychopathology, and grouped using cluster analysis. Associations between clusters and parents' level of education, functioning, caregiver status, child's level of stimulation and support in the home, and polygenic risk scores were examined. Results A total of four groups including one of broadly affected children were identified. The broadly affected group was represented 4–5-fold (18.1%) amongst FHR-SZ children and 2–3-fold (10.2%) amongst FHR-BP children, compared to controls (4.1%) (P

• Leonardsen, Esten Høyland; Peng, Han; Kaufmann, Tobias; Agartz, Ingrid; Andreassen, Ole & Celius, Elisabeth Gulowsen [Show all 19 contributors for this article] (2022). Deep neural networks learn general and clinically relevant representations of the ageing brain. NeuroImage. ISSN 1053-8119. 256. doi: 10.1016/j.neuroimage.2022.119210. Full text in Research Archive Show summary

  The discrepancy between chronological age and the apparent age of the brain based on neuroimaging data — the brain age delta — has emerged as a reliable marker of brain health. With an increasing wealth of data, approaches to tackle heterogeneity in data acquisition are vital. To this end, we compiled raw structural magnetic resonance images into one of the largest and most diverse datasets assembled (n=53542), and trained convolutional neural networks (CNNs) to predict age. We achieved state-of-the-art performance on unseen data from unknown scanners (n=2553), and showed that higher brain age delta is associated with diabetes, alcohol intake and smoking. Using transfer learning, the intermediate representations learned by our model complemented and partly outperformed brain age delta in predicting common brain disorders. Our work shows we can achieve generalizable and biologically plausible brain age predictions using CNNs trained on heterogeneous datasets, and transfer them to clinical use cases.

• Cheng, Weiqiu; Frei, Oleksandr; Meer, Dennis van der; Wang, Yunpeng; O`Connell, Kevin & Chu, Yunhan [Show all 20 contributors for this article] (2021). Genetic Association Between Schizophrenia and Cortical Brain Surface Area and Thickness. JAMA psychiatry. ISSN 2168-6238. 78(9), p. 1020–1030. doi: 10.1001/jamapsychiatry.2021.1435. Full text in Research Archive Show summary

  Importance Schizophrenia is a complex heritable disorder associated with many genetic variants, each with a small effect. While cortical differences between patients with schizophrenia and healthy controls are consistently reported, the underlying molecular mechanisms remain elusive. Objective To investigate the extent of shared genetic architecture between schizophrenia and brain cortical surface area (SA) and thickness (TH) and to identify shared genomic loci. Design, Setting, and Participants Independent genome-wide association study data on schizophrenia (Psychiatric Genomics Consortium and CLOZUK: n = 105 318) and SA and TH (UK Biobank: n = 33 735) were obtained. The extent of polygenic overlap was investigated using MiXeR. The specific shared genomic loci were identified by conditional/conjunctional false discovery rate analysis and were further examined in 3 independent cohorts. Data were collected from December 2019 to February 2021, and data analysis was performed from May 2020 to February 2021. Main Outcomes and Measures The primary outcomes were estimated fractions of polygenic overlap between schizophrenia, total SA, and average TH and a list of functionally characterized shared genomic loci. Results Based on genome-wide association study data from 139 053 participants, MiXeR estimated schizophrenia to be more polygenic (9703 single-nucleotide variants [SNVs]) than total SA (2101 SNVs) and average TH (1363 SNVs). Most SNVs associated with total SA (1966 of 2101 [93.6%]) and average TH (1322 of 1363 [97.0%]) may be associated with the development of schizophrenia. Subsequent conjunctional false discovery rate analysis identified 44 and 23 schizophrenia risk loci shared with total SA and average TH, respectively. The SNV associations of shared loci between schizophrenia and total SA revealed en masse concordant association between the discovery and independent cohorts. After removing high linkage disequilibrium regions, such as the major histocompatibility complex region, the shared loci were enriched in immunologic signature gene sets. Polygenic overlap and shared loci between schizophrenia and schizophrenia-associated regions of interest for SA (superior frontal and middle temporal gyri) and for TH (superior temporal, inferior temporal, and superior frontal gyri) were also identified. Conclusions and Relevance This study demonstrated shared genetic loci between cortical morphometry and schizophrenia, among which a subset are associated with immunity. These findings provide an insight into the complex genetic architecture and associated with schizophrenia.

• Vidal-Piñeiro, Didac; Wang, Yunpeng; Krogsrud, Stine Kleppe; Amlien, Inge; Baaré, William FC & Bartres-Faz, David [Show all 31 contributors for this article] (2021). Individual variations in ‘brain age’ relate to early-life factors more than to longitudinal brain change. eLIFE. 10. doi: 10.7554/eLife.69995. Full text in Research Archive Show summary

  Brain age is a widely used index for quantifying individuals’ brain health as deviation from a normative brain aging trajectory. Higher-than-expected brain age is thought partially to reflect above-average rate of brain aging. Here, we explicitly tested this assumption in two independent large test datasets (UK Biobank [main] and Lifebrain [replication]; longitudinal observations ≈ 2750 and 4200) by assessing the relationship between cross-sectional and longitudinal estimates of brain age. Brain age models were estimated in two different training datasets (n ≈ 38,000 [main] and 1800 individuals [replication]) based on brain structural features. The results showed no association between cross-sectional brain age and the rate of brain change measured longitudinally. Rather, brain age in adulthood was associated with the congenital factors of birth weight and polygenic scores of brain age, assumed to reflect a constant, lifelong influence on brain structure from early life. The results call for nuanced interpretations of cross-sectional indices of the aging brain and question their validity as markers of ongoing within-person changes of the aging brain. Longitudinal imaging data should be preferred whenever the goal is to understand individual change trajectories of brain and cognition in aging.

• Sun, Jiangming; Wang, Yunpeng; Folkersen, Lasse; Borne, Yan; Amlien, Inge & Buil, Alfonso [Show all 13 contributors for this article] (2021). Translating polygenic risk scores for clinical use by estimating the confidence bounds of risk prediction. Nature Communications. doi: 10.1038/s41467-021-25014-7. Full text in Research Archive Show summary

  A promise of genomics in precision medicine is to provide individualized genetic risk pre- dictions. Polygenic risk scores (PRS), computed by aggregating effects from many genomic variants, have been developed as a useful tool in complex disease research. However, the application of PRS as a tool for predicting an individual’s disease susceptibility in a clinical setting is challenging because PRS typically provide a relative measure of risk evaluated at the level of a group of people but not at individual level. Here, we introduce a machine-learning technique, Mondrian Cross-Conformal Prediction (MCCP), to estimate the confidence bounds of PRS-to-disease-risk prediction. MCCP can report disease status conditional probability value for each individual and give a prediction at a desired error level. Moreover, with a user-defined prediction error rate, MCCP can estimate the proportion of sample (coverage) with a correct prediction.

• Yuan, Xiuxia; Wang, Yunpeng; Li, Xue; Jiang, Jiajun; Kang, Yulin & Pang, Lijuan [Show all 13 contributors for this article] (2021). Gut microbial biomarkers for the treatment response in first-episode, drug-naïve schizophrenia: a 24-week follow-up study. Translational Psychiatry. 11, p. 1–9. doi: 10.1038/s41398-021-01531-3. Full text in Research Archive Show summary

  Preclinical studies have shown that the gut microbiota can play a role in schizophrenia (SCH) pathogenesis via the gut-brain axis. However, its role in the antipsychotic treatment response is unclear. Here, we present a 24-week follow-up study to identify gut microbial biomarkers for SCH diagnosis and treatment response, using a sample of 107 first-episode, drug-naïve SCH patients, and 107 healthy controls (HCs). We collected biological samples at baseline (all participants) and follow-up time points after risperidone treatment (SCH patients). Treatment response was assessed using the Positive and Negative Symptoms Scale total (PANSS-T) score. False discovery rate was used to correct for multiple testing. We found that SCH patients showed lower α-diversity (the Shannon and Simpson’s indices) compared to HCs at baseline (p = 1.21 × 10−9, 1.23 × 10−8, respectively). We also found a significant difference in β-diversity between SCH patients and HCs (p = 0.001). At baseline, using microbes that showed different abundance between patients and controls as predictors, a prediction model can distinguish patients from HCs with an area under the curve (AUC) of 0.867. In SCH patients, after 24 weeks of risperidone treatment, we observed an increase of α-diversity toward the basal level of HCs. At the genus level, we observed decreased abundance of Lachnoclostridium (p = 0.019) and increased abundance Romboutsia (p = 0.067). Moreover, the treatment response in SCH patients was significantly associated with the basal levels of Lachnoclostridium and Romboutsia (p = 0.005 and 0.006, respectively). Our results suggest that SCH patients may present characteristic microbiota, and certain microbiota biomarkers may predict treatment response in this patient population.

• Uddin, Md Jamal; Ekstrøm, Claus Thorn; Hemager, Nicoline; Christiani, Camilla A J; Gregersen, Maja & Ellersgaard, Ditte Vestbjerg [Show all 23 contributors for this article] (2021). Is the Association Between Parents’ Mental Illness and Child Psychopathology Mediated via Home Environment and Caregiver’s Psychosocial Functioning? A Mediation Analysis of the Danish High Risk and Resilience Study—VIA7, a Population-Based Cohort Study. Schizophrenia Bulletin Open. 2(1). doi: 10.1093/schizbullopen/sgab024. Full text in Research Archive
• Wang, Yunpeng; Grydeland, Håkon; Roe, James Michael; Pan, Mengyu; Magnussen, Fredrik & Amlien, Inge [Show all 17 contributors for this article] (2021). Associations of circulating C-reactive proteins, APOE ε4, and brain markers for Alzheimer’s disease in healthy samples across the lifespan. Brain, Behavior, and Immunity. ISSN 0889-1591. 100. doi: 10.1016/j.bbi.2021.12.008. Full text in Research Archive Show summary

  The apolipoprotein E gene ε4 allele (APOE ε4) and higher circulating level of C-reactive protein (CRP) have been extensively investigated as risk factors for Alzheimer’s disease (AD). Paradoxically, APOE ε4 has been associated with lower levels of blood CRP in middle-aged and older populations. However, few studies have investigated this intriguing relation and its impact on neurological markers for AD in younger ages, nor across the whole lifespan. Here, we examine associations of blood CRP levels, APOE ε4, and biomarkers for AD in a cognitively healthy lifespan cohort (N up to 749; 20–81 years of age) and replicate the findings in UK Biobank (N = 304 322; 37–72 years of age), the developmental ABCD study (N = 10 283; 9–11 years of age), and a middle-aged sample (N = 339; 40–65 years of age). Hippocampal volume, brain amyloid-β (Aβ) plaque levels, cerebrospinal fluid (CSF) levels of Aβ and tau species, and neurofilament protein light protein (NFL) were used as AD biomarkers in subsamples. In addition, we examined the genetic contribution to the variation of CRP levels over different CRP ranges using polygenic scores for CRP (PGS-CRP). Our results show APOE ε4 consistently associates with low blood CRP levels across all age groups (p < 0.05). Strikingly, both ε4 and PGS-CRP associated mainly with blood CRP levels within the low range (<5mg/L). We then show both APOE ε4 and high CRP levels associate with smaller hippocampus volumes across the lifespan (p < 0.025). APOE ε4 was associated with high Aβ plaque levels in the brain (FDR-corrected p = 8.69x10-4), low levels of CSF Aβ42 (FDR-corrected p = 6.9x10-2), and lower ratios of Aβ42 to Aβ40 (FDR-corrected p = 5.08x10-5). Blood CRP levels were weakly correlated with higher ratio of CSF Aβ42 to Aβ40 (p = 0.03, FDR-corrected p = 0.4). APOE ε4 did not correlate with blood concentrations of another 9 inflammatory cytokines, and none of these cytokines correlated with AD biomarkers.

• Amare, Azmeraw T.; Schubert, Klaus Oliver; Hou, Liping; Clark, Scott R.; Papiol, Sergi & Cearns, Micah [Show all 309 contributors for this article] (2021). Association of polygenic score for major depression with response to lithium in patients with bipolar disorder. Molecular Psychiatry. ISSN 1359-4184. 26(6), p. 2457–2470. doi: 10.1038/s41380-020-0689-5. Full text in Research Archive
• Fjell, Anders Martin; Grydeland, Håkon; Wang, Yunpeng; Amlien, Inge; Bartrés-Faz, David & Brandmaier, Andreas M. [Show all 24 contributors for this article] (2021). The genetic organization of longitudinal subcortical volumetric change is stable throughout the lifespan running title: Genetics of subcortical lifespan change. eLIFE. 10, p. 1–22. doi: 10.7554/eLife.66466. Full text in Research Archive Show summary

  Development and aging of the cerebral cortex show similar topographic organization and are governed by the same genes. It is unclear whether the same is true for subcortical regions, which follow fundamentally different ontogenetic and phylogenetic principles. We tested the hypothesis that genetically governed neurodevelopmental processes can be traced throughout life by assessing to which degree brain regions that develop together continue to change together through life. Analyzing over 6000 longitudinal MRIs of the brain, we used graph theory to identify five clusters of coordinated development, indexed as patterns of correlated volumetric change in brain structures. The clusters tended to follow placement along the cranial axis in embryonic brain development, suggesting continuity from prenatal stages, and correlated with cognition. Across independent longitudinal datasets, we demonstrated that developmental clusters were conserved through life. Twin-based genetic correlations revealed distinct sets of genes governing change in each cluster. Single-nucleotide polymorphisms-based analyses of 38,127 cross-sectional MRIs showed a similar pattern of genetic volume–volume correlations. In conclusion, coordination of subcortical change adheres to fundamental principles of lifespan continuity and genetic organization.

• Krogsrud, Stine Kleppe; Mowinckel, Athanasia Monika; Sederevicius, Donatas; Vidal-Piñeiro, Didac; Amlien, Inge Kasbohm & Wang, Yunpeng [Show all 9 contributors for this article] (2021). Relationships between apparent cortical thickness and working memory across the lifespan - Effects of genetics and socioeconomic status. Developmental Cognitive Neuroscience. ISSN 1878-9293. 51, p. 1–11. doi: 10.1016/j.dcn.2021.100997. Full text in Research Archive
• Li, Xue; Fan, Xiaoduo; Yuan, Xiuxia; Pang, Lijuan; Hu, Shaohua & Wang, Yunpeng [Show all 8 contributors for this article] (2021). The Role of Butyric Acid in Treatment Response in Drug-Naïve First Episode Schizophrenia. Frontiers in Psychiatry. 12. doi: 10.3389/fpsyt.2021.724664. Full text in Research Archive
• Grydeland, Håkon; Sederevicius, Donatas; Wang, Yunpeng; Bartres-Faz, David; Bertram, Lars & Dobricic, Valerija [Show all 16 contributors for this article] (2021). Self-Reported Sleep Relates to Microstructural Hippocampal Decline in β-Amyloid Positive Adults Beyond Genetic Risk. Sleep. ISSN 0161-8105. 44(11). doi: 10.1093/sleep/zsab110. Full text in Research Archive Show summary

  Background To test the hypothesis that worse self-reported sleep relates to memory decay and reduced hippocampal integrity as indexed by increased intra-hippocampal water diffusion, and that the relations are stronger in the presence of β-amyloid (Aβ) accumulation, a marker of Alzheimer’s disease (AD) pathology. Methods Two-hundred and forty-three cognitively healthy participants, aged 19-81 years, completed the Pittsburgh Sleep Quality Index, and 2 diffusion tensor imaging sessions, on average 3 years apart, allowing measures of decline in hippocampal microstructural integrity as indexed by increased mean diffusivity. We measured memory decay using delayed recall from the California Verbal Learning Test. 18F-Flutemetamol positron emission tomography, in 108 participants above 44 years of age, yielded 23 Aβ positive. Genotyping enabled controlling for APOE ε4 status, and polygenic scores for sleep efficiency and AD. Results Worse global sleep quality and sleep efficiency related to more rapid reduction in hippocampal microstructural integrity over time. Focusing on sleep efficiency, the relation was stronger in presence of Aβ accumulation. Sleep efficiency related to memory decay indirectly via hippocampal integrity decline. The results were not explained by genetic risk for sleep efficiency and AD. Conclusions Poor self-reported sleep efficiency related to decline in hippocampal integrity, especially in the presence of Aβ accumulation. Poor sleep and hippocampal microstructural decline may partly explain memory decline in older adults with Aβ pathology. The relationships were not explained by genetic risk. Poor self-reported sleep efficiency might constitute a risk factor for AD, although the causal mechanisms driving the of observed associations remain unknown.

• Maihofer, Adam X.; Choi, Karmel W.; Coleman, Jonathan R.I.; Daskalakis, Nikolaos P.; Denckla, Christy A. & Ketema, Elizabeth [Show all 181 contributors for this article] (2021). Enhancing Discovery of Genetic Variants for Posttraumatic Stress Disorder Through Integration of Quantitative Phenotypes and Trauma Exposure Information. Biological Psychiatry. ISSN 0006-3223. p. 1–11. doi: 10.1016/j.biopsych.2021.09.020. Full text in Research Archive Show summary

  Background Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs). Methods A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms. Results GWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program. Conclusions Through using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods.

• Blokland, Gabriella A. M.; Grove, Jakob; Chen, Chia-Yen; Cotsapas, Chris; Tobet, Stuart & Handa, Robert [Show all 50 contributors for this article] (2021). Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders. Biological Psychiatry. ISSN 0006-3223. 91, p. 102–117. doi: 10.1016/j.biopsych.2021.02.972. Full text in Research Archive Show summary

  Background Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. Methods We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. Results Across disorders, genome-wide significant single nucleotide polymorphism–by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10−8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10−6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10−7; rs73033497, p = 8.8 × 10−7; rs7914279, p = 6.4 × 10−7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10−7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10−7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10−7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). Conclusions In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.

• Andlauer, Till F.M.; Guzman-Parra, José; Streit, Fabian; Strohmaier, Jana; González, Maria José & Flores, Susana Gil [Show all 50 contributors for this article] (2021). Bipolar multiplex families have an increased burden of common risk variants for psychiatric disorders. Molecular Psychiatry. ISSN 1359-4184. 26, p. 1286–1298. doi: 10.1038/s41380-019-0558-2. Full text in Research Archive Show summary

  Multiplex families with a high prevalence of a psychiatric disorder are often examined to identify rare genetic variants with large effect sizes. In the present study, we analysed whether the risk for bipolar disorder (BD) in BD multiplex families is influenced by common genetic variants. Furthermore, we investigated whether this risk is conferred mainly by BD-specific risk variants or by variants also associated with the susceptibility to schizophrenia or major depression. In total, 395 individuals from 33 Andalusian BD multiplex families (166 BD, 78 major depressive disorder, 151 unaffected) as well as 438 subjects from an independent, BD case/control cohort (161 unrelated BD, 277 unrelated controls) were analysed. Polygenic risk scores (PRS) for BD, schizophrenia (SCZ), and major depression were calculated and compared between the cohorts. Both the familial BD cases and unaffected family members had higher PRS for all three psychiatric disorders than the independent controls, with BD and SCZ being significant after correction for multiple testing, suggesting a high baseline risk for several psychiatric disorders in the families. Moreover, familial BD cases showed significantly higher BD PRS than unaffected family members and unrelated BD cases. A plausible hypothesis is that, in multiplex families with a general increase in risk for psychiatric disease, BD development is attributable to a high burden of common variants that confer a specific risk for BD. The present analyses demonstrated that common genetic risk variants for psychiatric disorders are likely to contribute to the high incidence of affective psychiatric disorders in the multiplex families. However, the PRS explained only part of the observed phenotypic variance, and rare variants might have also contributed to disease development.

• Walhovd, Kristine Beate; Fjell, Anders Martin; Wang, Yunpeng; Amlien, Inge; Mowinckel, Athanasia Monika & Lindenberger, Ulman [Show all 29 contributors for this article] (2021). Education and income show heterogeneous relationships to lifespan brain and cognitive differences across European and US cohorts. Cerebral Cortex. ISSN 1047-3211. 32(4), p. 839–854. doi: 10.1093/cercor/bhab248. Full text in Research Archive Show summary

  Abstract Higher socio-economic status (SES) has been proposed to have facilitating and protective effects on brain and cognition. We ask whether relationships between SES, brain volumes and cognitive ability differ across cohorts, by age and national origin. European and US cohorts covering the lifespan were studied (4–97 years, N = 500 000; 54 000 w/brain imaging). There was substantial heterogeneity across cohorts for all associations. Education was positively related to intracranial (ICV) and total gray matter (GM) volume. Income was related to ICV, but not GM. We did not observe reliable differences in associations as a function of age. SES was more strongly related to brain and cognition in US than European cohorts. Sample representativity varies, and this study cannot identify mechanisms underlying differences in associations across cohorts. Differences in neuroanatomical volumes partially explained SES–cognition relationships. SES was more strongly related to ICV than to GM, implying that SES–cognition relations in adulthood are less likely grounded in neuroprotective effects on GM volume in aging. The relatively stronger SES–ICV associations rather are compatible with SES–brain volume relationships being established early in life, as ICV stabilizes in childhood. The findings underscore that SES has no uniform association with, or impact on, brain and cognition.

• Grasby, Katrina L.; Jahanshad, Neda; Painter, Jodie N; Colodro-Conde, Lucía; Bralten, Janita & Hibar, DP [Show all 50 contributors for this article] (2020). The genetic architecture of the human cerebral cortex. Science. ISSN 0036-8075. 367(6484). doi: 10.1126/science.aay6690. Full text in Research Archive Show summary

  INTRODUCTION The cerebral cortex underlies our complex cognitive capabilities. Variations in human cortical surface area and thickness are associated with neurological, psychological, and behavioral traits and can be measured in vivo by magnetic resonance imaging (MRI). Studies in model organisms have identified genes that influence cortical structure, but little is known about common genetic variants that affect human cortical structure. RATIONALE To identify genetic variants associated with human cortical structure at both global and regional levels, we conducted a genome-wide association meta-analysis of brain MRI data from 51,665 individuals across 60 cohorts. We analyzed the surface area and average thickness of the whole cortex and 34 cortical regions with known functional specializations. RESULTS We identified 306 nominally genome-wide significant loci (P < 5 × 10−8) associated with cortical structure in a discovery sample of 33,992 participants of European ancestry. Of the 299 loci for which replication data were available, 241 loci influencing surface area and 14 influencing thickness remained significant after replication, with 199 loci passing multiple testing correction (P < 8.3 × 10−10; 187 influencing surface area and 12 influencing thickness). Common genetic variants explained 34% (SE = 3%) of the variation in total surface area and 26% (SE = 2%) in average thickness; surface area and thickness showed a negative genetic correlation (rG = −0.32, SE = 0.05, P = 6.5 × 10−12), which suggests that genetic influences have opposing effects on surface area and thickness. Bioinformatic analyses showed that total surface area is influenced by genetic variants that alter gene regulatory activity in neural progenitor cells during fetal development. By contrast, average thickness is influenced by active regulatory elements in adult brain samples, which may reflect processes that occur after mid-fetal development, such as myelination, branching, or pruning. When considered together, these results support the radial unit hypothesis that different developmental mechanisms promote surface area expansion and increases in thickness. To identify specific genetic influences on individual cortical regions, we controlled for global measures (total surface area or average thickness) in the regional analyses. After multiple testing correction, we identified 175 loci that influence regional surface area and 10 that influence regional thickness. Loci that affect regional surface area cluster near genes involved in the Wnt signaling pathway, which is known to influence areal identity. We observed significant positive genetic correlations and evidence of bidirectional causation of total surface area with both general cognitive functioning and educational attainment. We found additional positive genetic correlations between total surface area and Parkinson’s disease but did not find evidence of causation. Negative genetic correlations were evident between total surface area and insomnia, attention deficit hyperactivity disorder, depressive symptoms, major depressive disorder, and neuroticism. CONCLUSION This large-scale collaborative work enhances our understanding of the genetic architecture of the human cerebral cortex and its regional patterning. The highly polygenic architecture of the cortex suggests that distinct genes are involved in the development of specific cortical areas. Moreover, we find evidence that brain structure is a key phenotype along the causal pathway that leads from genetic variation to differences in general cognitive function.

• Hofer, Edith; Roshchupkin, Gennady V.; Adams, Hieab H H; Knol, Maria J.; Lin, Honghuang & Li, Shuo [Show all 51 contributors for this article] (2020). Genetic correlations and genome-wide associations of cortical structure in general population samples of 22,824 adults. Nature Communications. 11. doi: 10.1038/s41467-020-18367-y. Full text in Research Archive Show summary

  Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.

• Palomera, Aldo Còrdova; Meer, Dennis van der; Kaufmann, Tobias; Bettella, Francesco; Wang, Yunpeng & Alnæs, Dag [Show all 40 contributors for this article] (2020). Genetic control of variability in subcortical and intracranial volumes. Molecular Psychiatry. ISSN 1359-4184. p. 1–8. doi: 10.1038/s41380-020-0664-1. Full text in Research Archive Show summary

  Sensitivity to external demands is essential for adaptation to dynamic environments, but comes at the cost of increased risk of adverse outcomes when facing poor environmental conditions. Here, we apply a novel methodology to perform genome-wide association analysis of mean and variance in ten key brain features (accumbens, amygdala, caudate, hippocampus, pallidum, putamen, thalamus, intracranial volume, cortical surface area, and cortical thickness), integrating genetic and neuroanatomical data from a large lifespan sample (n = 25,575 individuals; 8–89 years, mean age 51.9 years). We identify genetic loci associated with phenotypic variability in thalamus volume and cortical thickness. The variance-controlling loci involved genes with a documented role in brain and mental health and were not associated with the mean anatomical volumes. This proof-of-principle of the hypothesis of a genetic regulation of brain volume variability contributes to establishing the genetic basis of phenotypic variance (i.e., heritability), allows identifying different degrees of brain robustness across individuals, and opens new research avenues in the search for mechanisms controlling brain and mental health.

• Walhovd, Kristine B; Fjell, Anders Martin; Sørensen, Øystein; Mowinckel, Athanasia Monika; Reinbold, Céline Sonja & Idland, Ane-Victoria [Show all 12 contributors for this article] (2020). Genetic risk for Alzheimer disease predicts hippocampal volume through the human lifespan. Neurology: Genetics. 6(5). doi: 10.1212/NXG.0000000000000506. Full text in Research Archive Show summary

  Objective To test the hypothesis that genetic risk for Alzheimer disease (AD) may represent a stable influence on the brain from early in life, rather than being primarily age dependent, we investigated in a lifespan sample of 1,181 persons with a total of 2,690 brain scans, whether higher polygenic risk score (PGS) for AD and presence of APOE ε4 was associated with lower hippocampal volumes to begin with, as an offset effect, or possibly faster decline in older age. Methods Using general additive mixed models, we assessed the relations of PGS for AD, including variants in APOE with hippocampal volume and its change in a cognitively healthy longitudinal lifespan sample (age range: 4–95 years, mean visit age 39.7 years, SD 26.9 years), followed for up to 11 years. Results AD-PGS and APOE ε4 in isolation showed a significant negative effect on hippocampal volume. The effect of a 1 sample SD increase in AD-PGS on hippocampal volume was estimated to –36.4 mm 3 (confidence interval [CI]: –71.8, –1.04) and the effect of carrying ε4 allele(s) –107.0 mm 3 (CI: –182.0, –31.5). Offset effects of AD-PGS and APOE ε4 were present in hippocampal development, and interactions between age and genetic risk on volume change were not consistently observed. Conclusions Endophenotypic manifestation of polygenic risk for AD may be seen across the lifespan in cognitively healthy persons, not being confined to clinical populations or older age. This emphasizes that a broader population and age range may be relevant targets for attempts to prevent AD.

• Wang, Yunpeng; Nudel, Ron; Benros, Michael Eriksen; Skogstrand, Kristin; Fishilevich, Simon & Lancet, Doron [Show all 14 contributors for this article] (2020). Genome-wide association study identifies 16 genomic regions associated with circulating cytokines at birth. PLoS Genetics. ISSN 1553-7390. doi: 10.1371/journal.pgen.1009163. Full text in Research Archive Show summary

  Circulating inflammatory markers are essential to human health and disease, and they are often dysregulated or malfunctioning in cancers as well as in cardiovascular, metabolic, immunologic and neuropsychiatric disorders. However, the genetic contribution to the physiological variation of levels of circulating inflammatory markers is largely unknown. Here we report the results of a genome-wide genetic study of blood concentration of ten cytokines, including the hitherto unexplored calcium-binding protein (S100B). The study leverages a unique sample of neonatal blood spots from 9,459 Danish subjects from the iPSYCH initiative. We estimate the SNP-heritability of marker levels as ranging from essentially zero for Erythropoietin (EPO) up to 73% for S100B. We identify and replicate 16 associated genomic regions (p &lt; 5 x 10 −9 ), of which four are novel. We show that the associated variants map to enhancer elements, suggesting a possible transcriptional effect of genomic variants on the cytokine levels. The identification of the genetic architecture underlying the basic levels of cytokines is likely to prompt studies investigating the relationship between cytokines and complex disease. Our results also suggest that the genetic architecture of cytokines is stable from neonatal to adult life.

• Smeland, Olav Bjerkehagen; Shadrin, Alexey A.; Bahrami, Shahram; Broce, Iris J.; Tesli, Martin Steen & Frei, Oleksandr [Show all 22 contributors for this article] (2020). Genome-wide Association Analysis of Parkinson’s Disease and Schizophrenia Reveals Shared Genetic Architecture and Identifies Novel Risk Loci. Biological Psychiatry. ISSN 0006-3223. 89(3), p. 227–235. doi: 10.1016/j.biopsych.2020.01.026. Full text in Research Archive Show summary

  BACKGROUND:Parkinson’s disease (PD) and schizophrenia (SCZ) are heritable brain disorders that involvedysregulation of the dopaminergic system. Epidemiological studies have reported potential comorbidity between thedisorders, and movement disturbances are common in patients with SCZ before treatment with antipsychotic drugs.Despite this, little is known about shared genetic etiology between the disorders.METHODS:We analyzed recent large genome-wide association studies on patients with SCZ (N= 77,096) and PD(N= 417,508) using a conditional/conjunctional false discovery rate (FDR) approach to evaluate overlap incommon genetic variants and improve statistical power for genetic discovery. Using a variety of biologicalresources, we functionally characterized the identified genomic loci.RESULTS:We observed genetic enrichment in PD conditional onassociations with SCZ and vice versa, indicatingpolygenic overlap. We then leveraged this cross-trait enrichment using conditional FDR analysis and identified 9 novel PDrisk loci and 1 novel SCZ locus at conditional FDR,.01. Furthermore, we identified 9 genomic loci jointly associated withPD and SCZ at conjunctional FDR,.05. There was an even distribution of antagonistic and agonistic effect directionsamong the shared loci, in line with the insignificant genetic correlation between the disorders. Of 67 genes mapped to theshared loci, 65 are expressed in the human brain and show cell type–specific expression profiles.CONCLUSIONS:Altogether, the study increases understanding of the genetic architectures underlying SCZ and PD,indicating that common molecular genetic mechanisms may contribute to overlapping pathophysiological and clinicalfeatures between the disorders.

• Fjell, Anders Martin; Sederevicius, Donatas; Sneve, Markus Handal; Lange, Ann-Marie Glasø de; Bråthen, Anne Cecilie Sjøli & Idland, Ane-Victoria [Show all 16 contributors for this article] (2020). Self-reported sleep problems are related to amyloid deposition in cortical regions with high HOMER1 gene expression. Cerebral Cortex. ISSN 1047-3211. 30(4), p. 2144–2156. doi: 10.1093/cercor/bhz228. Full text in Research Archive Show summary

  Sleep problems are related to the elevated levels of the Alzheimer’s disease (AD) biomarker β-amyloid (Aβ). Hypotheses about the causes of this relationship can be generated from molecular markers of sleep problems identified in rodents. A major marker of sleep deprivation is Homer1a, a neural protein coded by the HOMER1 gene, which has also been implicated in brain Aβ accumulation. Here, we tested whether the relationship between cortical Aβ accumulation and self-reported sleep quality, as well as changes in sleep quality over 3 years, was stronger in cortical regions with high HOMER1 mRNA expression levels. In a sample of 154 cognitively healthy older adults, Aβ correlated with poorer sleep quality cross-sectionally and longitudinally (n = 62), but more strongly in the younger than in older individuals. Effects were mainly found in regions with high expression of HOMER1. The anatomical distribution of the sleep-Aβ relationship followed closely the Aβ accumulation pattern in 69 patients with mild cognitive impairment or AD. Thus, the results indicate that the relationship between sleep problems and Aβ accumulation may involve Homer1 activity in the cortical regions, where harbor Aβ deposits in AD. The findings may advance our understanding of the relationship between sleep problems and AD risk.

• Coleman, Jonathan R.I.; Gaspar, Helena A; Bryois, Julien; Byrne, Enda M; Forstner, Andreas J & Holmans, Peter A [Show all 51 contributors for this article] (2020). The Genetics of the Mood Disorder Spectrum: Genome-wide Association Analyses of More Than 185,000 Cases and 439,000 Controls. Biological Psychiatry. ISSN 0006-3223. doi: 10.1016/j.biopsych.2019.10.015. Full text in Research Archive Show summary

  Background: Mood disorders (including major depressive disorder and bipolar disorder) affect 10% to 20% of the population. They range from brief, mild episodes to severe, incapacitating conditions that markedly impact lives. Multiple approaches have shown considerable sharing of risk factors across mood disorders despite their diagnostic distinction. Methods: To clarify the shared molecular genetic basis of major depressive disorder and bipolar disorder and to highlight disorder-specific associations, we meta-analyzed data from the latest Psychiatric Genomics Consortium genome-wide association studies of major depression (including data from 23andMe) and bipolar disorder, and an additional major depressive disorder cohort from UK Biobank (total: 185,285 cases, 439,741 controls; nonoverlapping N = 609,424). Results: Seventy-three loci reached genome-wide significance in the meta-analysis, including 15 that are novel for mood disorders. More loci from the Psychiatric Genomics Consortium analysis of major depression than from that for bipolar disorder reached genome-wide significance. Genetic correlations revealed that type 2 bipolar disorder correlates strongly with recurrent and single-episode major depressive disorder. Systems biology analyses highlight both similarities and differences between the mood disorders, particularly in the mouse brain cell types implicated by the expression patterns of associated genes. The mood disorders also differ in their genetic correlation with educational attainment-the relationship is positive in bipolar disorder but negative in major depressive disorder. Conclusions: The mood disorders share several genetic associations, and genetic studies of major depressive disorder and bipolar disorder can be combined effectively to enable the discovery of variants not identified by studying either disorder alone. However, we demonstrate several differences between these disorders. Analyzing subtypes of major depressive disorder and bipolar disorder provides evidence for a genetic mood disorders spectrum.

• Coleman, Jonathan R. I.; Peyrot, Wouter J.; Purves, Kirstin L.; Davis, Katrina A. S.; Rayner, Christopher & Choi, Shing Wan [Show all 215 contributors for this article] (2020). Genome-wide gene-environment analyses of major depressive disorder and reported lifetime traumatic experiences in UK Biobank. Molecular Psychiatry. ISSN 1359-4184. 25(7), p. 1430–1446. doi: 10.1038/s41380-019-0546-6. Full text in Research Archive
• Shen, Xueyi; Howard, David M.; Adams, Mark J.; Hill, W. David; Clarke, Toni-Kim & McIntosh, Andrew M. [Show all 202 contributors for this article] (2020). A phenome-wide association and Mendelian Randomisation study of polygenic risk for depression in UK Biobank. Nature Communications. 11(1). doi: 10.1038/s41467-020-16022-0. Full text in Research Archive
• Tao, Qi; Miao, Yun; Li, Huihui; Yuan, Xiuxia; Huang, Xufeng & Wang, Yunpeng [Show all 10 contributors for this article] (2020). Insulin Resistance and Oxidative Stress: In Relation to Cognitive Function and Psychopathology in Drug-Naïve, First-Episode Drug-Free Schizophrenia. Frontiers in Psychiatry. doi: 10.3389/fpsyt.2020.537280. Full text in Research Archive Show summary

  Objective: The present study aimed to examine whether insulin resistance and oxidative stress are associated with cognitive impairment in first-episode drug-free schizophrenia (SZ) patients. Methods: Ninety first-episode SZ patients and 70 healthy controls were enrolled. Fasting insulin (FINS) and markers of oxidative stress [oxidized glutathione (GSSG), superoxide dismutase (SOD), nitric oxide (NO) and uric acid (UA) levels] were measured in serum before pharmacological treatment was initiated. Psychiatric symptoms and cognitive function were assessed with the Positive and Negative Syndrome Scale (PANSS) and MATRICS Consensus Cognitive Battery (MCCB), respectively. In addition, the homeostatic model assessment of insulin resistance (HOMA-IR) was also studied. Results: HOMA-IR and serum levels of GSSG and NO were significantly higher in SZ patients than in healthy controls ( P &amp;lt; 0.001), while the serum levels of SOD were significantly lower than in healthy controls ( P &amp;lt; 0.001). HOMA-IR, GSSG and NO levels were significantly correlated to the total cognitive function scores of the patient group ( r = −0.345,−0.369,−0.444, respectively, P &amp;lt; 0.05). But these factors were not co-related to the cognitive functions in the healthy control group. And, levels of SOD, UA were not associated with the total cognitive function scores in both the patient and the healthy control groups. NO was positively correlated with general pathological and the total score in the PANSS, and was negatively correlated with six cognitive domains ( r = −0.316 to −0.553, P &amp;lt; 0.05). Conclusions: The levels of insulin resistance and oxidative stress are elevated, and correlated with the severity of cognitive impairment in drug-naïve, first-episode SZ patients. Treatment approaches targeting on reducing insulin resistance and oxidative stress may improve cognitive function in SZ patients.

• Stahl, Eli A.; Breen, Gerome; Forstner, Andreas J.; McQuillin, Andrew; Ripke, Stephan & Trubetskoy, Vassily [Show all 277 contributors for this article] (2019). Genome-wide association study identifies 30 loci associated with bipolar disorder. Nature Genetics. ISSN 1061-4036. 51(5), p. 793–803. doi: 10.1038/s41588-019-0397-8. Full text in Research Archive Show summary

  Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10−4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10−8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.

• Nievergelt, Caroline M.; Maihofer, Adam X.; Klengel, Torsten; Atkinson, Elizabeth G.; Chen, Chia-Yen & Choi, Karmel W. [Show all 179 contributors for this article] (2019). International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci. Nature Communications. 10:4558, p. 1–16. doi: 10.1038/s41467-019-12576-w. Full text in Research Archive Show summary

  The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5–20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson’s disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations.

• Wang, Yunpeng; Karstoft, Karen-Inge; Nievergelt, Caroline M.; Maihofer, Adam X.; Stein, Murray B. & Ursano, Robert J. [Show all 13 contributors for this article] (2019). Post-traumatic stress following military deployment: Genetic associations and cross-disorder genetic correlations. Journal of Affective Disorders. ISSN 0165-0327. 252, p. 350–357. doi: 10.1016/j.jad.2019.04.070. Full text in Research Archive
• Drange, Ole Kristian; Smeland, Olav Bjerkehagen; Shadrin, Alexey A.; Finseth, Per Ivar; Witoelar, Aree & Frei, Oleksandr [Show all 52 contributors for this article] (2019). Genetic Overlap Between Alzheimer’s Disease and Bipolar Disorder Implicates the MARK2 and VAC14 Genes. Frontiers in Neuroscience. ISSN 1662-4548. 13. doi: 10.3389/fnins.2019.00220. Full text in Research Archive Show summary

  Background: Alzheimer’s disease (AD) and bipolar disorder (BIP) are complex traits influenced by numerous common genetic variants, most of which remain to be detected. Clinical and epidemiological evidence suggest that AD and BIP are related. However, it is not established if this relation is of genetic origin. Here, we applied statistical methods based on the conditional false discovery rate (FDR) framework to detect genetic overlap between AD and BIP and utilized this overlap to increase the power to identify common genetic variants associated with either or both traits. Methods: We obtained genome wide association studies data from the International Genomics of Alzheimer’s Project part 1 (17,008 AD cases and 37,154 controls) and the Psychiatric Genetic Consortium Bipolar Disorder Working Group (20,352 BIP cases and 31,358 controls). We used conditional QQ-plots to assess overlap in common genetic variants between AD and BIP. We exploited the genetic overlap to re-rank test-statistics for AD and BIP and improve detection of genetic variants using the conditional FDR framework. Results: Conditional QQ-plots demonstrated a polygenic overlap between AD and BIP. Using conditional FDR, we identified one novel genomic locus associated with AD, and nine novel loci associated with BIP. Further, we identified two novel loci jointly associated with AD and BIP implicating the MARK2 gene (lead SNP rs10792421, conjunctional FDR = 0.030, same direction of effect) and the VAC14 gene (lead SNP rs11649476, conjunctional FDR = 0.022, opposite direction of effect). Conclusion: We found polygenic overlap between AD and BIP and identified novel loci for each trait and two jointly associated loci. Further studies should examine if the shared loci implicating the MARK2 and VAC14 genes could explain parts of the shared and distinct features of AD and BIP.

• Nudel, Ron; Wang, Yunpeng; Appadurai, Vivek; Schork, Andrew J.; Buil, Alfonso & Agerbo, Esben [Show all 16 contributors for this article] (2019). A large-scale genomic investigation of susceptibility to infection and its association with mental disorders in the Danish population. Translational Psychiatry. 9, p. 1–10. doi: 10.1038/s41398-019-0622-3. Full text in Research Archive
• Bauer, Anna E.; Liu, Xiaoqin; Byrne, Enda M.; Sullivan, Patrick F.; Wray, Naomi R. & Agerbo, Esben [Show all 21 contributors for this article] (2019). Genetic risk scores for major psychiatric disorders and the risk of postpartum psychiatric disorders. Translational Psychiatry. 9:288, p. 1–12. doi: 10.1038/s41398-019-0629-9. Full text in Research Archive
• Choi, Karmel W.; Chen, Chia-Yen; Stein, Murray B.; Klimentidis, Yann C.; Wang, Min-Jung & Koenen, Karestan C. [Show all 203 contributors for this article] (2019). Assessment of bidirectional relationships between physical activity and depression among adults a 2-sample Mendelian randomization study. JAMA psychiatry. ISSN 2168-6238. 76(4), p. 399–408. doi: 10.1001/jamapsychiatry.2018.4175. Full text in Research Archive
• Gasse, Christiane; Wimberley, Theresa; Wang, Yunpeng; Mors, Ole; Børglum, Anders & Als, Thomas Damm [Show all 10 contributors for this article] (2019). Schizophrenia polygenic risk scores, urbanicity and treatment-resistant schizophrenia. Schizophrenia Research. ISSN 0920-9964. 212, p. 79–85. doi: 10.1016/j.schres.2019.08.008. Full text in Research Archive
• Frei, Oleksandr; Holland, Dominic; Smeland, Olav Bjerkehagen; Shadrin, Alexey A.; Fan, Chun Chieh & Mæland, Steffen [Show all 12 contributors for this article] (2019). Bivariate causal mixture model quantifies polygenic overlap between complex traits beyond genetic correlation. Nature Communications. 10(1). doi: 10.1038/s41467-019-10310-0. Full text in Research Archive Show summary

  Accumulating evidence from genome wide association studies (GWAS) suggests an abundance of shared genetic influences among complex human traits and disorders, such as mental disorders. Here we introduce a statistical tool, MiXeR, which quantifies polygenic overlap irrespective of genetic correlation, using GWAS summary statistics. MiXeR results are presented as a Venn diagram of unique and shared polygenic components across traits. At 90% of SNP-heritability explained for each phenotype, MiXeR estimates that 8.3 K variants causally influence schizophrenia and 6.4 K influence bipolar disorder. Among these variants, 6.2 K are shared between the disorders, which have a high genetic correlation. Further, MiXeR uncovers polygenic overlap between schizophrenia and educational attainment. Despite a genetic correlation close to zero, the phenotypes share 8.3 K causal variants, while 2.5 K additional variants influence only educational attainment. By considering the polygenicity, discoverability and heritability of complex phenotypes, MiXeR analysis may improve our understanding of cross-trait genetic architectures.

• Jansen, Iris E.; Savage, Jeanne E.; Watanabe, Kyoko; Bryois, Julien; Williams, Dylan M. & Steinberg, Stacy [Show all 53 contributors for this article] (2019). Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk. Nature Genetics. ISSN 1061-4036. 51(3), p. 404–413. doi: 10.1038/s41588-018-0311-9. Full text in Research Archive Show summary

  Alzheimer’s disease (AD) is highly heritable and recent studies have identified over 20 disease-associated genomic loci. Yet these only explain a small proportion of the genetic variance, indicating that undiscovered loci remain. Here, we performed a large genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 cases, 383,378 controls). AD-by-proxy, based on parental diagnoses, showed strong genetic correlation with AD (rg = 0.81). Meta-analysis identified 29 risk loci, implicating 215 potential causative genes. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver, and microglia). Gene-set analyses indicate biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomization results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD.

• Lee, Phil H.; Antilla, Verneri; Won, Hyejung; Feng, Yen-Chen A.; Rosenthal, Jacob & Zhu, Zhaozhong [Show all 66 contributors for this article] (2019). Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders. Cell. ISSN 0092-8674. 179(7), p. 1469–1482. doi: 10.1016/j.cell.2019.11.020. Full text in Research Archive Show summary

  Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed a meta-analysis of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders identifying three groups of inter-related disorders. We detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning in the second trimester prenatally, and play prominent roles in a suite of neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.

• Jong, Simone de; Diniz, Mateus Jose Abdalla; Saloma, Andiara; Gadelha, Ary; Santoro, Marcos L. & Ota, Vanessa K. [Show all 22 contributors for this article] (2018). Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder. Communications Biology. 1(163). doi: 10.1038/s42003-018-0155-y. Full text in Research Archive Show summary

  Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders.

• Bonham, Luke W.; Karch, Celeste M.; Fan, Chun C.; Tan, Chin; Geier, Ethan G. & Wang, Yunpeng [Show all 25 contributors for this article] (2018). CXCR4 involvement in neurodegenerative diseases. Translational Psychiatry. 8:73, p. 1–10. doi: 10.1038/s41398-017-0049-7. Full text in Research Archive Show summary

  Neurodegenerative diseases likely share common underlying pathobiology. Although prior work has identified susceptibility loci associated with various dementias, few, if any, studies have systematically evaluated shared genetic risk across several neurodegenerative diseases. Using genome-wide association data from large studies (total n = 82,337 cases and controls), we utilized a previously validated approach to identify genetic overlap and reveal common pathways between progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), Parkinson’s disease (PD) and Alzheimer’s disease (AD). In addition to the MAPT H1 haplotype, we identified a variant near the chemokine receptor CXCR4 that was jointly associated with increased risk for PSP and PD. Using bioinformatics tools, we found strong physical interactions between CXCR4 and four microglia related genes, namely CXCL12, TLR2, RALB, and CCR5. Evaluating gene expression from post-mortem brain tissue, we found that expression of CXCR4 and microglial genes functionally related to CXCR4 was dysregulated across a number of neurodegenerative diseases. Furthermore, in a mouse model of tauopathy, expression of CXCR4 and functionally associated genes was significantly altered in regions of the mouse brain that accumulate neurofibrillary tangles most robustly. Beyond MAPT, we show dysregulation of CXCR4 expression in PSP, PD, and FTD brains, and mouse models of tau pathology. Our multi-modal findings suggest that abnormal signaling across a ‘network’ of microglial genes may contribute to neurodegeneration and may have potential implications for clinical trials targeting immune dysfunction in patients with neurodegenerative diseases.

• Zhang, Qian; Liang, Zhe; Cui, Xuean; Ji, Changmian; Li, Yun & Zhang, Pingxian [Show all 16 contributors for this article] (2018). N6-methyladenine DNA methylation in Japonica and Indica rice genomes and its association with gene expression, plant development, and stress responses. Molecular Plant. ISSN 1674-2052. 11(12), p. 1492–1508. doi: 10.1016/j.molp.2018.11.005. Full text in Research Archive
• Chen, Chao; Meng, Qingtuan; Xia, Yan; Ding, Chaodong; Wang, Le & Dai, Rujia [Show all 27 contributors for this article] (2018). The transcription factor POU3F2 regulates a gene coexpression network in brain tissue from patients with psychiatric disorders. Science Translational Medicine. ISSN 1946-6234. 10:eaat8178(472), p. 1–11. doi: 10.1126/scitranslmed.aat8178. Full text in Research Archive
• Alnæs, Dag; Kaufmann, Tobias; Doan, Nhat Trung; Palomera, Aldo Còrdova; Wang, Yunpeng & Bettella, Francesco [Show all 9 contributors for this article] (2018). Association of Heritable Cognitive Ability and Psychopathology With White Matter Properties in Children and Adolescents. JAMA psychiatry. ISSN 2168-6238. 75(3), p. 287–295. doi: 10.1001/jamapsychiatry.2017.4277. Full text in Research Archive
• Wray, Naomi R.; Ripke, Stephan; Mattheisen, Manuel; Trzaskowski, MacIej; Byrne, Enda M. & Abdellaoui, Abdel [Show all 216 contributors for this article] (2018). Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression. Nature Genetics. ISSN 1061-4036. 50(5), p. 668–681. doi: 10.1038/s41588-018-0090-3. Full text in Research Archive
• Erlangsen, Annette; Appadurai, Vivek; Wang, Yunpeng; Turecki, Gustavo; Mors, Ole & Werge, Thomas [Show all 17 contributors for this article] (2018). Genetics of suicide attempts in individuals with and without mental disorders: a population-based genome-wide association study. Molecular Psychiatry. ISSN 1359-4184. p. 1–12. doi: 10.1038/s41380-018-0218-y. Full text in Research Archive
• Consorti, Bipolar Sczhizophrenia Psychiatric Genomics; Ruderfer, Douglas M.; Ripke, Stephan; McQuillin, Andrew; Boocock, James & Stahl, Eli A. [Show all 52 contributors for this article] (2018). Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes. Cell. ISSN 0092-8674. 173(7), p. 1705–1715. doi: 10.1016/j.cell.2018.05.046. Full text in Research Archive
• Bettella, Francesco; Brown, AA; Smeland, Olav Bjerkehagen; Wang, Yunpeng; Witoelar, Aree & Demur, AA Buil [Show all 11 contributors for this article] (2018). Cross-tissue eQTL enrichment of associations in schizophrenia. PLOS ONE. 13(9). doi: 10.1371/journal.pone.0202812. Full text in Research Archive Show summary

  The genome-wide association study of the Psychiatric Genomics Consortium identified over one hundred schizophrenia susceptibility loci. The number of non-coding variants discovered suggests that gene regulation could mediate the effect of these variants on disease. Expression quantitative trait loci (eQTLs) contribute to variation in levels of mRNA. Given the co-occurrence of schizophrenia and several traits not involving the central nervous system (CNS), we investigated the enrichment of schizophrenia associations among eQTLs for four non-CNS tissues: adipose tissue, epidermal tissue, lymphoblastoid cells and blood. Significant enrichment was seen in eQTLs of all tissues: adipose (β = 0.18, p = 8.8 × 10−06), epidermal (β = 0.12, p = 3.1 × 10−04), lymphoblastoid (β = 0.19, p = 6.2 × 10−08) and blood (β = 0.19, p = 6.4 × 10−06). For comparison, we looked for enrichment of association with traits of known relevance to one or more of these tissues (body mass index, height, rheumatoid arthritis, systolic blood pressure and type-II diabetes) and found that schizophrenia enrichment was of similar scale to that observed when studying diseases in the context of a more likely causal tissue. To further investigate tissue specificity, we looked for differential enrichment of eQTLs with relevant Roadmap affiliation (enhancers and promoters) and varying distance from the transcription start site. Neither factor significantly contributed to the enrichment, suggesting that this is equally distributed in tissue-specific and cross-tissue regulatory elements. Our analyses suggest that functional correlates of schizophrenia risk are prevalent in non-CNS tissues. This could be because of pleiotropy or the effectiveness of variants affecting expression in different contexts. This suggests the utility of large, single-tissue eQTL experiments to increase eQTL discovery power in the study of schizophrenia, in addition to smaller, multiple-tissue approaches. Our results conform to the notion that schizophrenia is a systemic disorder involving many tissues.

• Srinivasan, Saurabh; Bettella, Francesco; Frei, Oleksandr; Hill, W. David; Wang, Yunpeng & Witoelar, Aree [Show all 17 contributors for this article] (2018). Enrichment of genetic markers of recent human evolution in educational and cognitive traits. Scientific Reports. 8:12585, p. 1–9. doi: 10.1038/s41598-018-30387-9. Full text in Research Archive Show summary

  Higher cognitive functions are regarded as one of the main distinctive traits of humans. Evidence for the cognitive evolution of human beings is mainly based on fossil records of an expanding cranium and an increasing complexity of material culture artefacts. However, the molecular genetic factors involved in the evolution are still relatively unexplored. Here, we investigated whether genomic regions that underwent positive selection in humans after divergence from Neanderthals are enriched for genetic association with phenotypes related to cognitive functions. We used genome wide association data from a study of college completion (N = 111,114), one of educational attainment (N = 293,623) and two different studies of general cognitive ability (N = 269,867 and 53,949). We found nominally significant polygenic enrichment of associations with college completion (p = 0.025), educational attainment (p = 0.043) and general cognitive ability (p = 0.015 and 0.025, respectively), suggesting that variants influencing these phenotypes are more prevalent in evolutionarily salient regions. The enrichment remained significant after controlling for other known genetic enrichment factors, and for affiliation to genes highly expressed in the brain. These findings support the notion that phenotypes related to higher order cognitive skills typical of humans have a recent genetic component that originated after the separation of the human and Neanderthal lineages.

• Li, Wen; Fan, Chun Chieh; Mäki-Marttunen, Tuomo; Thompson, Wesley Kurt; Schork, Andrew J. & Bettella, Francesco [Show all 10 contributors for this article] (2018). A molecule-based genetic association approach implicates a range of voltage-gated calcium channels associated with schizophrenia. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics. ISSN 1552-4841. 177(4), p. 454–467. doi: 10.1002/ajmg.b.32634. Full text in Research Archive
• Palomera, Aldo Còrdova; Kaufmann, Tobias; Bettella, Francesco; Wang, Yunpeng; Doan, Nhat Trung & Meer, Dennis van der [Show all 12 contributors for this article] (2018). Effects of autozygosity and schizophrenia polygenic risk on cognitive and brain developmental trajectories. European Journal of Human Genetics. ISSN 1018-4813. 26(7), p. 1049–1059. doi: 10.1038/s41431-018-0134-2. Full text in Research Archive
• Maier, Robert M.; Zhu, Zhihong; Lee, Sang Hong; Trzaskowski, Maciej; Ruderfer, Douglas M. & Stahl, Eli A. [Show all 17 contributors for this article] (2018). Improving genetic prediction by leveraging genetic correlations among human diseases and traits. Nature Communications. 9:989, p. 1–17. doi: 10.1038/s41467-017-02769-6. Full text in Research Archive
• Seibert, Tyler M.; Fan, Chun Chieh; Wang, Yunpeng; Zuber, Verena; Karunamuni, Roshan & Parsons, J. Kellogg [Show all 62 contributors for this article] (2018). Polygenic hazard score to guide screening for aggressive prostate cancer: development and validation in large scale cohorts. The BMJ. 360:j5757, p. 1–7. doi: 10.1136/bmj.j5757. Full text in Research Archive Show summary

  Objectives: To develop and validate a genetic tool to predict age of onset of aggressive prostate cancer (PCa) and to guide decisions of who to screen and at what age. Design: Analysis of genotype, PCa status, and age to select single nucleotide polymorphisms (SNPs) associated with diagnosis. These polymorphisms were incorporated into a survival analysis to estimate their effects on age at diagnosis of aggressive PCa (that is, not eligible for surveillance according to National Comprehensive Cancer Network guidelines; any of Gleason score ≥7, stage T3-T4, PSA (prostate specific antigen) concentration ≥10 ng/L, nodal metastasis, distant metastasis). The resulting polygenic hazard score is an assessment of individual genetic risk. The final model was applied to an independent dataset containing genotype and PSA screening data. The hazard score was calculated for these men to test prediction of survival free from PCa. Results: In the independent validation set, the hazard score calculated from 54 single nucleotide polymorphisms was a highly significant predictor of age at diagnosis of aggressive cancer (z=11.2, P<10−16). When men in the validation set with high scores (>98th centile) were compared with those with average scores (30th-70th centile), the hazard ratio for aggressive cancer was 2.9 (95% confidence interval 2.4 to 3.4). Inclusion of family history in a combined model did not improve prediction of onset of aggressive PCa (P=0.59), and polygenic hazard score performance remained high when family history was accounted for. Additionally, the positive predictive value of PSA screening for aggressive PCa was increased with increasing polygenic hazard score. Conclusions: Polygenic hazard scores can be used for personalised genetic risk estimates that can predict for age at onset of aggressive PCa.

• Sønderby, Ida Elken; Gustafsson, Omar; Doan, Nhat Trung; Hibar, Derrek; Martin-Brevet, Sandra & Espeseth, Thomas [Show all 15 contributors for this article] (2018). Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia. Molecular Psychiatry. ISSN 1359-4184. p. 1–16. doi: 10.1038/s41380-019-0358-8. Full text in Research Archive Show summary

  Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = −0.71 to −1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = −0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10−6, 1.7 × 10−9, 3.5 × 10−12 and 1.0 × 10−4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes.

• Witoelar, Aree; Rongve, Arvid; Almdahl, Ina Selseth; Ulstein, Ingun; Engvig, Andreas & White, Linda Rosemary [Show all 33 contributors for this article] (2018). Meta-analysis of Alzheimer’s disease on 9,751 samples from Norway and IGAP study identifies four risk loci. Scientific Reports. 8(1). doi: 10.1038/s41598-018-36429-6. Full text in Research Archive Show summary

  A large fraction of genetic risk factors for Alzheimer’s Disease (AD) is still not identified, limiting the understanding of AD pathology and study of therapeutic targets. We conducted a genome-wide association study (GWAS) of AD cases and controls of European descent from the multi-center DemGene network across Norway and two independent European cohorts. In a two-stage process, we first performed a meta-analysis using GWAS results from 2,893 AD cases and 6,858 cognitively normal controls from Norway and 25,580 cases and 48,466 controls from the International Genomics of Alzheimer’s Project (IGAP), denoted the discovery sample. Second, we selected the top hits (p < 1 × 10−6) from the discovery analysis for replication in an Icelandic cohort consisting of 5,341 cases and 110,008 controls. We identified a novel genomic region with genome-wide significant association with AD on chromosome 4 (combined analysis OR = 1.07, p = 2.48 x 10-8). This finding implicated HS3ST1, a gene expressed throughout the brain particularly in the cerebellar cortex. In addition, we identified IGHV1-68 in the discovery sample, previously not associated with AD. We also associated USP6NL/ECHDC3 and BZRAP1-AS1 to AD, confirming findings from a follow-up transethnic study. These new gene loci provide further evidence for AD as a polygenic disorder, and suggest new mechanistic pathways that warrant further investigation.

• Broce, Iris J.; Karch, Celeste M.; Wen, Natalie; Fan, Chun C.; Wang, Yunpeng & Tan, Chin Hong [Show all 29 contributors for this article] (2018). Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies. PLoS Medicine. ISSN 1549-1277. 15:e1002487(1), p. 1–20. doi: 10.1371/journal.pmed.1002487. Full text in Research Archive Show summary

  Background: Converging evidence suggests that immune-mediated dysfunction plays an important role in the pathogenesis of frontotemporal dementia (FTD). Although genetic studies have shown that immune-associated loci are associated with increased FTD risk, a systematic investigation of genetic overlap between immune-mediated diseases and the spectrum of FTD-related disorders has not been performed. Methods and findings: Using large genome-wide association studies (GWASs) (total n = 192,886 cases and controls) and recently developed tools to quantify genetic overlap/pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with FTD-related disorders—namely, FTD, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS)—and 1 or more immune-mediated diseases including Crohn disease, ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), and psoriasis. We found up to 270-fold genetic enrichment between FTD and RA, up to 160-fold genetic enrichment between FTD and UC, up to 180-fold genetic enrichment between FTD and T1D, and up to 175-fold genetic enrichment between FTD and CeD. In contrast, for CBD and PSP, only 1 of the 6 immune-mediated diseases produced genetic enrichment comparable to that seen for FTD, with up to 150-fold genetic enrichment between CBD and CeD and up to 180-fold enrichment between PSP and RA. Further, we found minimal enrichment between ALS and the immune-mediated diseases tested, with the highest levels of enrichment between ALS and RA (up to 20-fold). For FTD, at a conjunction false discovery rate < 0.05 and after excluding SNPs in linkage disequilibrium, we found that 8 of the 15 identified loci mapped to the human leukocyte antigen (HLA) region on Chromosome (Chr) 6. We also found novel candidate FTD susceptibility loci within LRRK2 (leucine rich repeat kinase 2), TBKBP1 (TBK1 binding protein 1), and PGBD5 (piggyBac transposable element derived 5). Functionally, we found that the expression of FTD–immune pleiotropic genes (particularly within the HLA region) is altered in postmortem brain tissue from patients with FTD and is enriched in microglia/macrophages compared to other central nervous system cell types. The main study limitation is that the results represent only clinically diagnosed individuals. Also, given the complex interconnectedness of the HLA region, we were not able to define the specific gene or genes on Chr 6 responsible for our pleiotropic signal. Conclusions: We show immune-mediated genetic enrichment specifically in FTD, particularly within the HLAregion. Our genetic results suggest that for a subset of patients, immune dysfunction may contribute to FTD risk. These findings have potential implications for clinical trials targeting immune dysfunction in patients with FTD.

• Zuber, Verena; Jönsson, Erik Gunnar; Frei, Oleksandr; Witoelar, Aree; Thompson, Wesley Kurt & Schork, Andrew J. [Show all 18 contributors for this article] (2018). Identification of shared genetic variants between schizophrenia and lung cancer. Scientific Reports. 674(8), p. 1–8. doi: 10.1038/s41598-017-16481-4. Full text in Research Archive Show summary

  Epidemiology studies suggest associations between schizophrenia and cancer. However, the underlying genetic mechanisms are not well understood, and difficult to identify from epidemiological data. We investigated if there is a shared genetic architecture between schizophrenia and cancer, with the aim to identify specific overlapping genetic loci. First, we performed genome-wide enrichment analysis and second, we analyzed specific loci jointly associated with schizophrenia and cancer by the conjunction false discovery rate. We analyzed the largest genome-wide association studies of schizophrenia and lung, breast, prostate, ovary, and colon-rectum cancer including more than 220,000 subjects, and included genetic association with smoking behavior. Polygenic enrichment of associations with lung cancer was observed in schizophrenia, and weak enrichment for the remaining cancer sites. After excluding the major histocompatibility complex region, we identified three independent loci jointly associated with schizophrenia and lung cancer. The strongest association included nicotinic acetylcholine receptors and is an established pleiotropic locus shared between lung cancer and smoking. The two other loci were independent of genetic association with smoking. Functional analysis identified downstream pleiotropic effects on epigenetics and gene-expression in lung and brain tissue. These findings suggest that genetic factors may explain partly the observed epidemiological association of lung cancer and schizophrenia.

• Hellard, Stephanie Le; Wang, Yunpeng; Witoelar, Aree; Zuber, Verena; Bettella, Francesco & Hugdahl, Kenneth [Show all 15 contributors for this article] (2017). Identification of gene loci that overlap between schizophrenia and educational attainment. Schizophrenia Bulletin. ISSN 0586-7614. 43(3), p. 654–664. doi: 10.1093/schbul/sbw085. Full text in Research Archive
• Srinivasan, Saurabh; Bettella, Francesco; Hassani, Sahar; Wang, Yunpeng; Witoelar, Aree & Schork, Andrew J. [Show all 13 contributors for this article] (2017). Probing the association between early evolutionary markers and schizophrenia. PLOS ONE. 12:e0169227(1), p. 1–15. doi: 10.1371/journal.pone.0169227. Full text in Research Archive
• Lo, Min-Tzu; Wang, Yunpeng; Kauppi, Karolina; Sanyal, Nilotpal; Fan, Chun-Chieh & Smeland, Olav Bjerkehagen [Show all 13 contributors for this article] (2017). Modeling prior information of common genetic variants improves gene discovery for neuroticism. Human Molecular Genetics. ISSN 0964-6906. 26(22), p. 4530–4539. doi: 10.1093/hmg/ddx340. Full text in Research Archive
• Joshi, Peter K.; Pirastu, Nicola; Kentistou, Katherine A.; Fischer, Krista; Hofer, Edith & Schraut, Katharina E. [Show all 113 contributors for this article] (2017). Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity. Nature Communications. 8:910(1), p. 1–13. doi: 10.1038/s41467-017-00934-5. Full text in Research Archive
• Smeland, Olav Bjerkehagen; Frei, Oleksandr; Kauppi, Karolina; Hill, W. David; Li, Wen & Wang, Yunpeng [Show all 22 contributors for this article] (2017). Identification of genetic loci jointly influencing schizophrenia risk and the cognitive traits of verbal-numerical reasoning, reaction time, and general cognitive function. JAMA psychiatry. ISSN 2168-6238. 74(10), p. 1065–1075. doi: 10.1001/jamapsychiatry.2017.1986. Full text in Research Archive Show summary

  Importance: Schizophrenia is associated with widespread cognitive impairments. Although cognitive deficits are one of the factors most strongly associated with functional outcome in schizophrenia, current treatment strategies largely fail to ameliorate these impairments. To develop more efficient treatment strategies in patients with schizophrenia, a better understanding of the pathogenesis of these cognitive deficits is needed. Accumulating evidence indicates that genetic risk of schizophrenia may contribute to cognitive dysfunction. Objective: To identify genomic regions jointly influencing schizophrenia and the cognitive domains of reaction time and verbal-numerical reasoning, as well as general cognitive function, a phenotype that captures the shared variation in performance across cognitive domains. Design, Setting, and Participants: Combining data from genome-wide association studies from multiple phenotypes using conditional false discovery rate analysis provides increased power to discover genetic variants and could elucidate shared molecular genetic mechanisms. Data from the following genome-wide association studies, published from July 24, 2014, to January 17, 2017, were combined: schizophrenia in the Psychiatric Genomics Consortium cohort (n = 79 757 [cases, 34 486; controls, 45 271]); verbal-numerical reasoning (n = 36 035) and reaction time (n = 111 483) in the UK Biobank cohort; and general cognitive function in CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) (n = 53 949) and COGENT (Cognitive Genomics Consortium) (n = 27 888). Main Outcomes and Measures: Genetic loci identified by conditional false discovery rate analysis. Brain messenger RNA expression and brain expression quantitative trait locus functionality were determined. Results: Among the participants in the genome-wide association studies, 21 loci jointly influencing schizophrenia and cognitive traits were identified: 2 loci shared between schizophrenia and verbal-numerical reasoning, 6 loci shared between schizophrenia and reaction time, and 14 loci shared between schizophrenia and general cognitive function. One locus was shared between schizophrenia and 2 cognitive traits and represented the strongest shared signal detected (nearest gene TCF20; chromosome 22q13.2), and was shared between schizophrenia (z score, 5.01; P = 5.53 × 10−7), general cognitive function (z score, –4.43; P = 9.42 × 10−6), and verbal-numerical reasoning (z score, –5.43; P = 5.64 × 10−8). For 18 loci, schizophrenia risk alleles were associated with poorer cognitive performance. The implicated genes are expressed in the developmental and adult human brain. Replicable expression quantitative trait locus functionality was identified for 4 loci in the adult human brain. Conclusions and Relevance: The discovered loci improve the understanding of the common genetic basis underlying schizophrenia and cognitive function, suggesting novel molecular genetic mechanisms.

• Smeland, Olav Bjerkehagen; Wang, Yunpeng; Lo, Min-Tzu; Li, Wen; Frei, Oleksandr & Witoelar, Aree [Show all 13 contributors for this article] (2017). Identification of genetic loci shared between schizophrenia and the Big Five personality traits. Scientific Reports. 7:2222(1), p. 1–9. doi: 10.1038/s41598-017-02346-3. Full text in Research Archive Show summary

  Schizophrenia is associated with differences in personality traits, and recent studies suggest that personality traits and schizophrenia share a genetic basis. Here we aimed to identify specific genetic loci shared between schizophrenia and the Big Five personality traits using a Bayesian statistical framework. Using summary statistics from genome-wide association studies (GWAS) on personality traits in the 23andMe cohort (n = 59,225) and schizophrenia in the Psychiatric Genomics Consortium cohort (n = 82,315), we evaluated overlap in common genetic variants. The Big Five personality traits neuroticism, extraversion, openness, agreeableness and conscientiousness were measured using a web implementation of the Big Five Inventory. Applying the conditional false discovery rate approach, we increased discovery of genetic loci and identified two loci shared between neuroticism and schizophrenia and six loci shared between openness and schizophrenia. The study provides new insights into the relationship between personality traits and schizophrenia by highlighting genetic loci involved in their common genetic etiology.

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• Kvalvik, Eirik Haugland; Røgeberg, Ole; Wang, Yunpeng & Lyngstad, Torkild Hovde (2024). Triangulating Evidence of Declining Heritability Across Educational Levels in Norway: Insights from Twin Models and Polygenic Scores. Behavior Genetics. ISSN 0001-8244. 54(6), p. 483–483. doi: 10.1007/s10519-024-10197-8. Full text in Research Archive Show summary

  Although the genetic basis for educational attainment has been extensively studied, the progression from high school to doctoral levels remains less understood. Therefore this study employs a sequential hurdle model for analyses of twin models (N = 8910, cohorts 1965–2001) and polygenic scores (PGS, N = 114,699, cohorts 1965–1989) to explore the additive genetic effects (A) for these educational transitions across Norwegian cohorts. Findings indicate that genetic influence decreases with higher educational hurdles: for high school graduates, A = 0.6 [0.39, 0.76]; for bachelor’s degree holders, A = 0.49 [0.36, 0.64]; for master’s degree holders, A = 0.42 [0.23, 0.61]; and for doctorate holders, A = 0.3 [0.02, 0.6]. Similarly, McFadden’s pseudo R2 from PGS revealed decreasing genetic influence from high school (0.047 [0.044, 0.051]) to PhD (0.01 [0.007, 0.013]). The study also finds a selection effect, where individuals with higher PGS are more likely to surpass educational milestones, evidenced by the adjusted mean standardized PGS increasing almost linearly with educational level, from high school (- 0.29 [- 0.3, - 0.28]) to PhD (0.72 [0.67, 0.76]). This suggests that for each educational hurdle passed, the less genetic influences matter for passing the next hurdle, but that there is a selection process where individuals with higher PGS tend to more easily pass higher educational hurdles.

• Iakunchykova, Olena; Benros, Michael E. & Wang, Yunpeng (2024). Author reply – Letter to the Editor “elevated C-reactive protein and IL-6 signalling are not the only determinants of sleep quality and duration”. Brain, Behavior, and Immunity - Health (BBI - Health). doi: 10.1016/j.bbih.2024.100785. Full text in Research Archive
• Iakunchykova, Olena; Schirmer, Henrik; Vangberg, Torgil Riise; Wang, Yunpeng; Benavente, Ernest Diez & Es, Rene Van [Show all 11 contributors for this article] (2023). Machine-learning derived measures of vascular and brain age are independently associated with cognitive function. European Journal of Preventive Cardiology (EJPC). ISSN 2047-4873. Full text in Research Archive
• Coleman, Jonathan R. I.; Peyrot, Wouter J.; Purves, Kirstin L.; Davis, Katrina A. S.; Rayner, Christopher & Choi, Shing Wan [Show all 223 contributors for this article] (2021). Correction: Genome-wide gene-environment analyses of major depressive disorder and reported lifetime traumatic experiences in UK Biobank (Molecular Psychiatry, (2020), 25, 7, (1430-1446), 10.1038/s41380-019-0546-6). Molecular Psychiatry. ISSN 1359-4184. 26(9), p. 5465–5465. doi: 10.1038/s41380-020-0779-4. Full text in Research Archive
• Smeland, Olav Bjerkehagen; Frei, Oleksandr; Wang, Yunpeng; Dale, Anders & Andreassen, Ole Andreas (2017). Combined Analysis of Large Genetic Samples. New Statistical Approaches Improve Gene Discovery. Full text in Research Archive
• Smeland, Olav Bjerkehagen; Frei, Oleksandr; Wang, Yunpeng; Fan, Chun Chieh; Shadrin, Alexey A. & Li, Wen [Show all 13 contributors for this article] (2017). C-Reactive Protein Levels and Schizophrenia Share Genetic Influences. Full text in Research Archive

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