Thomas Espeseth

• Korbmacher, Max; Lie, Ingrid Anne; Wesnes, Kristin; Westman, Eric; Espeseth, Thomas & Andreassen, Ole [Show all 13 contributors for this article] (2026). Regional patterns of grey matter volume decline in relapsing-remitting multiple sclerosis relative to healthy ageing. NeuroImage. ISSN 1053-8119. 338, p. 1–9. doi: 10.1016/j.neuroimage.2026.122118. Full text in Research Archive Show summary

  Background: Grey matter volume loss (GM-VL) is an accurate marker of multiple sclerosis (MS)-related progression. However, long-term comparisons of GM-VL between MS and healthy controls (HC) are rare, and the brain regions with most significant GM-VL and their clinical importance still need robust and longitudinal validation. Methods: This multi-cohort longitudinal observational study used two relapsing remitting MS (RRMS) cohorts (N = 386, T1w-scans=940) sampled for up-to-12 years to localise grey matter volume loss (GM-VL) and disease progression (Expanded Disability Status Scale (EDSS), Paced Auditory Serial Addition Test (PASAT), Fatigue Severity Scale (FSS)). The identified region-specific significant GM-VL was compared with 2163 HCs (T1w-scans=4326). Results: The strongest, replicable, significant patterns of brain GM-VL in RRMS were found in the frontal lobes, specifically, in the superior frontal cortex (SFC, βage≤-0.27), pars orbitalis (βage≤-0.25), and thalami (βage≤-0.20). Compared with healthy controls (HCs) >20 years older, MS showed greater GM-VL in the right SFC, caudal-middle frontal cortex, caudate, and left frontal pole (all Z > 2.08, p < 0.019). The overlap of associations between volumetric and clinical outcome changes was limited to EDSS, which was significantly related to left hippocampal volumes βEDSS≤-0.19 in both cohorts. Conclusions: Our findings indicate GM-VL in people with RRMS comparable to 20-year older HC, and stronger in the SFC and thalamus, and cohort-specific relationships with disability-progression.

• Bøen, Rune; Ørbeck, Beate; Hansen, Berit Hjelde; Skirbekk, Anne Benedicte; Kristensen, Hanne & Tamnes, Christian Krog [Show all 7 contributors for this article] (2026). Characterizing Attention and Cognitive Control Profiles of Children With ADHD and Anxiety. Journal of Attention Disorders. ISSN 1087-0547. doi: 10.1177/10870547261430076. Full text in Research Archive
• Lu, Zheng An; Ploner, Alexander; Birgegård, Andreas; Consortium, Eating Disorders Working Group of the Psychiatric Genomics; Landén, Mikael & Bulik, Cynthia M. [Show all 222 contributors for this article] (2025). Leveraging transdiagnostic genetic liability to psychiatric disorders to dissect clinical outcomes of anorexia nervosa. Molecular Psychiatry. ISSN 1359-4184. 31, p. 1475–1484. doi: 10.1038/s41380-025-03264-x. Full text in Research Archive Show summary

  Anorexia nervosa (AN) has extensive genetic correlations with other psychiatric disorders, and genetic risk for different psychiatric disorders was associated with distinct clinical courses in AN. Uncovering associations between transdiagnostic psychiatric genetic liability and AN outcomes can facilitate its personalized treatment. In this study, we investigated the associations between transdiagnostic psychiatric genetic liability and outcomes of AN. Genomic structural equation models were fitted to genome-wide association data for AN and psychiatric disorders with high genetic correlations with AN (obsessive-compulsive symptoms [OCS], major depressive disorder [MDD], schizophrenia, and anxiety disorders) to extract one shared and five trait-specific genetic components. Next, we calculated the polygenic risk scores (PRS) for these components, including PRSshared, PRSAN-specific, PRSOCS-specific, PRSMDD-specific, PRSSCZ-specific and PRSANX-specific, which index the shared genetic liability to all five psychiatric traits, and genetic liability specific to AN, OCS, MDD, SCZ and ANX, respectively. We then tested associations between these PRSs and clinical outcomes reported between 1997 and 2018 among AN cases from the Anorexia Nervosa Genetics Initiative (ANGI), linked to Swedish National Registers. The clinical outcomes included cumulative disease burden (i.e., number of diagnoses, medication prescriptions, and inpatient days), risks of psychiatric comorbidities, and AN symptomatology. Among 4028 included AN cases, the mean (SD) birth year was 1985 (9), and 3947 (98.0%) were female. Within AN, +1 SD increase of PRSshared was associated with 9–39% excess risk of disease burden and psychiatric comorbidity, whereas the associations between PRSAN-specific and most clinical outcomes were statistically non-significant. +1 SD increase of PRSMDD-specific was associated with 3–29% increased risk of AN disease burden. Our findings show that shared psychiatric liability is associated with more adverse AN outcomes, whereas AN-specific liability is not a good indicator for its clinical course. This study provides a novel perspective on factors influencing heterogeneity in AN clinical course.

• Silva, Ana I.; Sønderby, Ida Elken; Kirov, George; Abdellaoui, Abdel; Agartz, Ingrid & Ames, David [Show all 106 contributors for this article] (2025). Penetrance of Neurodevelopmental Copy Number Variants Is Associated With Variations in Cortical Morphology. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging. ISSN 2451-9022. 10(10), p. 1093–1106. doi: 10.1016/j.bpsc.2025.05.010. Full text in Research Archive Show summary

  Background: Copy number variants (CNVs) may increase the risk for neurodevelopmental conditions. The neurobiological mechanisms that link these high-risk genetic variants to clinical phenotypes are largely unknown. An important question is whether brain abnormalities in individuals who carry CNVs are associated with their degree of penetrance. Methods: We investigated whether increased CNV penetrance for schizophrenia and other developmental disorders was associated with variations in cortical and subcortical morphology. We pooled T1-weighted brain magnetic resonance imaging and genetic data from 22 cohorts from the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis)-CNV consortium. In the main analyses, we included 9268 individuals (aged 7–90 years, 54% female), from which we identified 398 carriers of 36 neurodevelopmental CNVs at 20 distinct loci. A secondary analysis was performed including additional neuroimaging data from the ENIGMA-22q consortium, including 274 carriers of the 22q11.2 deletion and 291 noncarriers. CNV penetrance was estimated through penetrance scores that were previously generated from large cohorts of patients and controls. These scores represent the probability risk of developing either schizophrenia or other developmental disorders (including developmental delay, autism spectrum disorder, and congenital malformations). Results: For both schizophrenia and developmental disorders, increased penetrance scores were associated with lower surface area in the cerebral cortex and lower intracranial volume. For both conditions, associations between CNV-penetrance scores and cortical surface area were strongest in regions of the occipital lobes, specifically in the cuneus and lingual gyrus. Conclusions: Our findings link global and regional cortical morphometric features with CNV penetrance, providing new insights into neurobiological mechanisms of genetic risk for schizophrenia and other developmental disorders.

• Korbmacher, Max; Lie, Ingrid Anne; Wesnes, Kristin; Westman, Eric; Espeseth, Thomas & Specht, Karsten [Show all 12 contributors for this article] (2025). Multimodal predictors of disability progression and processing speed decline in relapsing–remitting multiple sclerosis. Scientific Reports. 15(1), p. 1–13. doi: 10.1038/s41598-025-17894-2. Full text in Research Archive Show summary

  The underlying mechanisms for neurodegeneration in multiple sclerosis are complex and incompletely understood. Multivariate and multimodal investigations integrating demographic, clinical, multi-omics, and neuroimaging data provide opportunities for nuanced analyses, aimed to define disease progression markers. We used data from a 12-year longitudinal multicenter cohort of 88 people with multiple sclerosis, to test the predictive value of multi-omics, T 1 -weighted MRI (lesion count and volume, lesion-filled brain-predicted age), clinical examinations, self-reports on quality of life, demographics, and general health-related variables for future functional and cognitive disability. Systematic increases in Expanded Disability Status Scale (EDSS) scores were used to stratify a progressive disability group (PDG) from relatively stabile disability. A processing speed decline group (PSDG) was defined by a ≥ 20% decrease of Paced Auditory Serial Addition Test score from previous timepoints. We used a multiverse approach to identify which baseline variables were most predictive for PDG and PSDG memberships, considering multiple analysis paths. Future disability (median area under the curve: mAUC = 0.83 ± 0.04, median Brier score: mBS = 0.16 ± 0.02) and the loss of processing speed (mAUC = 0.89 ± 0.05, mBS = 0.10 ± 0.03) could be successfully classified across models. Varibles significantly (median p-values < 0.05) predicting stable disability included receiving disease modifying treatment at 12-year follow-up (median Odds Ratio: mOR PDG = 7.44 ± 4.07, p median = 0.013, proportion of the OR’s directionality: PORSD = 100%), lower baseline EDSS for each 1-unit (mOR PDG = 0.25 ± 0.11, p median = 0.013, PORSD = 100%), and counter-intuitively every year increase in baseline age (mOR PDG = 1.12 ± 0.04, p median = 0.020, PORSD = 100%), and lower vitamin A per 1 umol/L (mOR PDG = 0.10 ± 0.05, p median = 0.016, PORSD = 99.7%) and D levels per 1 nmol/L (mOR PDG = 0.95 ± 0.02, p median = 0.025, PORSD = 100%). Variables significantly predicting stable processing speed were receiving disease modifying treatment at 12-year follow-up (mOR PSDG = 0.10 ± 0.08, p median = 0.013, PORSD = 100%) and baseline PASAT score (mOR PSDG = 0.86 ± 0.03, p median = 0.005, PORSD = 99.73%). These findings were supported by an additional simulation study. Concordant with the literature, disease modifying treatments influence disability progression, as well as a higher EDSS and PASAT scores at measurement start. Experimental and counterintuitive findings on vitamin A and D levels require further validation. The large variability across models suggests a strong influence of analytic flexibility, such as the selection of covariates.

• Knol, Maria J.; Poot, Raymond A.; Evans, Tavia E.; Satizabal, Claudia L.; Mishra, Aniket & Sargurupremraj, Muralidharan [Show all 304 contributors for this article] (2024). Genetic variants for head size share genes and pathways with cancer. Cell Reports Medicine. 5(5). doi: 10.1016/j.xcrm.2024.101529. Full text in Research Archive
• García-Marín, Luis M.; Campos, Adrian I.; Diaz-Torres, Santiago; Rabinowitz, Jill A.; Ceja, Zuriel & Mitchell, Brittany L. [Show all 190 contributors for this article] (2024). Genomic analysis of intracranial and subcortical brain volumes yields polygenic scores accounting for variation across ancestries. Nature Genetics. ISSN 1061-4036. 56(11), p. 2333–2344. doi: 10.1038/s41588-024-01951-z. Full text in Research Archive
• Ruuskanen, Veera; Hagen, Thomas; Espeseth, Thomas & Mathôt, Sebastiaan (2024). Baseline Pupil Size Seems Unrelated to Fluid Intelligence, Working Memory Capacity, and Attentional Control. The Journal of Cognition. 7(1). doi: 10.5334/joc.365. Full text in Research Archive
• Bøen, Rune; Kaufmann, Tobias Herbert; Meer, Dennis van der; Frei, Oleksandr; Agartz, Ingrid & Ames, David [Show all 53 contributors for this article] (2023). Beyond the Global Brain Differences: Intraindividual Variability Differences in 1q21.1 Distal and 15q11.2 BP1-BP2 Deletion Carriers. Biological Psychiatry. ISSN 0006-3223. 95(2), p. 147–160. doi: 10.1016/j.biopsych.2023.08.018. Full text in Research Archive Show summary

  Background Carriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and global brain differences compared with noncarriers. However, interpreting regional differences is challenging if a global difference drives the regional brain differences. Intraindividual variability measures can be used to test for regional differences beyond global differences in brain structure. Methods Magnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n = 30) and duplication (n = 27) and 15q11.2 BP1-BP2 deletion (n = 170) and duplication (n = 243) carriers and matched noncarriers (n = 2350). Regional intra-deviation scores, i.e., the standardized difference between an individual’s regional difference and global difference, were used to test for regional differences that diverge from the global difference. Results For the 1q21.1 distal deletion carriers, cortical surface area for regions in the medial visual cortex, posterior cingulate, and temporal pole differed less and regions in the prefrontal and superior temporal cortex differed more than the global difference in cortical surface area. For the 15q11.2 BP1-BP2 deletion carriers, cortical thickness in regions in the medial visual cortex, auditory cortex, and temporal pole differed less and the prefrontal and somatosensory cortex differed more than the global difference in cortical thickness. Conclusions We find evidence for regional effects beyond differences in global brain measures in 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants. The results provide new insight into brain profiling of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants, with the potential to increase understanding of the mechanisms involved in altered neurodevelopment.

• Herrebrøden, Henrik; Espeseth, Thomas & Bishop, Laura (2023). Mental Effort in Elite and Nonelite Rowers. Journal of Sport & Exercise Psychology (JSEP). ISSN 0895-2779. 45(4), p. 208–223. doi: 10.1123/jsep.2022-0164. Full text in Research Archive Show summary

  Mental effort (intensity of attention) in elite sports has remained a debated topic and a challenging phenomenon to measure. Thus, a quasi-ecological laboratory study was conducted to investigate mental effort in elite rowers as compared with a group of nonelites. Findings suggest that eye-tracking measures—specifically, blink rates and pupil size—can serve as valid indicators of mental effort in physically demanding sport tasks. Furthermore, findings contradict the notion that elite athletes spend less cognitive effort than their lower-level peers. Specifically, elites displayed similar levels of self-reported effort and performance decrement with increasing mental load and significantly more mental effort overall as measured by pupil-size increase (relative to baseline) during rowing trials as compared with the nonelites in the sample. Future studies on eye tracking in sports may include investigations of mental effort in addition to selective attention during physically demanding tasks.

• Korbmacher, Max; Wang, Mengyun; Eikeland, Rune; Buchert, Ralph; Andreassen, Ole & Espeseth, Thomas [Show all 10 contributors for this article] (2023). Considerations on brain age predictions from repeatedly sampled data across time. Brain and Behavior. doi: 10.1002/brb3.3219. Full text in Research Archive Show summary

  Introduction Brain age, the estimation of a person's age from magnetic resonance imaging (MRI) parameters, has been used as a general indicator of health. The marker requires however further validation for application in clinical contexts. Here, we show how brain age predictions perform for the same individual at various time points and validate our findings with age-matched healthy controls. Methods We used densely sampled T1-weighted MRI data from four individuals (from two densely sampled datasets) to observe how brain age corresponds to age and is influenced by acquisition and quality parameters. For validation, we used two cross-sectional datasets. Brain age was predicted by a pretrained deep learning model. Results We found small within-subject correlations between age and brain age. We also found evidence for the influence of field strength on brain age which replicated in the cross-sectional validation data and inconclusive effects of scan quality. Conclusion The absence of maturation effects for the age range in the presented sample, brain age model bias (including training age distribution and field strength), and model error are potential reasons for small relationships between age and brain age in densely sampled longitudinal data. Clinical applications of brain age models should consider of the possibility of apparent biases caused by variation in the data acquisition process.

• Herrebrøden, Henrik; Jensenius, Alexander Refsum; Espeseth, Thomas; Bishop, Laura & Vuoskoski, Jonna Katariina (2023). Cognitive load causes kinematic changes in both elite and non-elite rowers. Human Movement Science. ISSN 0167-9457. 90. doi: 10.1016/j.humov.2023.103113. Full text in Research Archive Show summary

  The current motor literature suggests that extraneous cognitive load may affect performance and kinematics in a primary motor task. A common response to increased cognitive demand, as observed in past studies, might be to reduce movement complexity and revert to previously learned movement patterns, in line with the progression-regression hypothesis. However, according to several accounts of automaticity, motor experts should be able to cope with dual task demands without detriment to their performance and kinematics. To test this, we conducted an experiment asking elite and non-elite rowers to use a rowing ergometer under conditions of varying task load. We employed single-task conditions with low cognitive load (i.e., rowing only) and dual-task conditions with high cognitive load (i.e., rowing and solving arithmetic problems). The results of the cognitive load manipulations were mostly in line with our hypotheses. Overall, participants reduced movement complexity, for example by reverting towards tighter coupling of kinematic events, in their dual-task performance as compared to single-task performance. The between-group kinematic differences were less clear. In contradiction to our hypotheses, we found no significant interaction between skill level and cognitive load, suggesting that the rowers' kinematics were affected by cognitive load irrespective of skill level. Overall, our findings contradict several past findings and automaticity theories, and suggest that attentional resources are required for optimal sports performance.

• Kraft, Pål; Kraft, Brage; Hagen, Thomas & Espeseth, Thomas (2022). Subjective Socioeconomic Status, Cognitive Abilities, and Personal Control: Associations With Health Behaviours. Frontiers in Psychology. 12. doi: 10.3389/fpsyg.2021.784758. Full text in Research Archive
• Frangou, Sophia; Modabbernia, Amirhossein; Williams, Steven C. R.; Papachristou, Efstathios; Doucet, Gaëlle E. & Agartz, Ingrid [Show all 63 contributors for this article] (2022). Cortical thickness across the lifespan: Data from 17,075 healthy individuals aged 3-90 years. Human Brain Mapping. ISSN 1065-9471. 43(1), p. 431–451. doi: 10.1002/hbm.25364. Full text in Research Archive Show summary

  Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3–90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes.

• Dima, Danai; Modabbernia, Amirhossein; Papachristou, Efstathios; Doucet, Gaëlle E.; Agartz, Ingrid & Aghajani, Moji [Show all 52 contributors for this article] (2022). Subcortical volumes across the lifespan: Data from 18,605 healthy individuals aged 3–90 years. Human Brain Mapping. ISSN 1065-9471. 43(1), p. 452–469. doi: 10.1002/hbm.25320. Full text in Research Archive Show summary

  Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine age-related trajectories inferred from cross-sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3–90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter-individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age-related morphometric patterns.

• Brouwer, Rachel M.; Klein, Marieke; Grasby, Katrina L.; Schnack, Hugo G.; Jahanshad, Neda & Teeuw, Jalmar [Show all 200 contributors for this article] (2022). Genetic variants associated with longitudinal changes in brain structure across the lifespan. Nature Neuroscience. ISSN 1097-6256. 25(4), p. 421–432. doi: 10.1038/s41593-022-01042-4. Full text in Research Archive
• 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.

• Bølstad, Evalill; Havighurst, Sophie S.; Tamnes, Christian K.; Nygaard, Egil; Bjørk, Rune Flaaten & Stavrinou, Maria [Show all 7 contributors for this article] (2021). A Pilot Study of a Parent Emotion Socialization Intervention: Impact on Parent Behavior, Child Self-Regulation, and Adjustment. Frontiers in Psychology. 12, p. 1–15. doi: 10.3389/fpsyg.2021.730278. Full text in Research Archive Show summary

  Adequate emotion regulation in children is crucial for healthy development and is influenced by parent emotion socialization. The current pilot study aimed to test, for the first time in a Scandinavian population, whether an emotion-focused intervention, Tuning in to Kids (TIK), had positive effects on parent emotion-related socialization behaviors (ERSBs), and children's self-regulation, anxiety, and externalizing behavior problems. We conducted a controlled trial of the 6-week evidence-based TIK parenting program with 20 parents of preschool children aged 5–6 years and 19 wait-list controls. Assessments at baseline and 6 months after the intervention included parent-report questionnaires on parent ERSBs and child adjustment, as well as aspects of children's self-regulation assessed with two behavioral tasks, the Emotional Go/No-Go task (EGNG) and the AX-Continuous Performance Task (AX-CPT). Results showed a significant increase in reported parent emotion coaching behavior and an uncorrected significant decrease in parents' report of child externalizing problems in intervention participants compared to controls. The behavioral data showed an uncorrected significant improvement in child emotion discrimination in the control condition compared to the intervention condition, while measures of children's executive control improved from baseline to follow-up for both conditions but were not significantly different between conditions. These findings suggest that this emotion-focused parenting intervention contributed to improvement in parents' emotion coaching and their appraisal of child externalizing problems, while children's self-regulation showed mainly normative developmental improvements. Further research with a larger sample will be the next step to determine if these pilot findings are seen in an adequately powered study.

• Polushina, Tatiana; Banerjee, Niladri; Giddaluru, Sudheer; Bettella, Francesco; Espeseth, Thomas & Lundervold, Astri J. [Show all 13 contributors for this article] (2021). Identification of pleiotropy at the gene level between psychiatric disorders and related traits. Translational Psychiatry. 11(1). doi: 10.1038/s41398-021-01530-4. Full text in Research Archive Show summary

  Major mental disorders are highly prevalent and make a substantial contribution to the global disease burden. It is known that mental disorders share clinical characteristics, and genome-wide association studies (GWASs) have recently provided evidence for shared genetic factors as well. Genetic overlaps are usually identified at the single-marker level. Here, we aimed to identify genetic overlaps at the gene level between 7 mental disorders (schizophrenia, autism spectrum disorder, major depressive disorder, anorexia nervosa, ADHD, bipolar disorder and anxiety), 8 brain morphometric traits, 2 cognitive traits (educational attainment and general cognitive function) and 9 personality traits (subjective well-being, depressive symptoms, neuroticism, extraversion, openness to experience, agreeableness and conscientiousness, children’s aggressive behaviour, loneliness) based on publicly available GWASs. We performed systematic conditional regression analyses to identify independent signals and select loci associated with more than one trait. We identified 48 genes containing independent markers associated with several traits (pleiotropy at the gene level). We also report 9 genes with different markers that show independent associations with single traits (allelic heterogeneity). This study demonstrates that mental disorders and related traits do show pleiotropy at the gene level as well as the single-marker level. The identification of these genes might be important for prioritizing further deep genotyping, functional studies, or drug targeting.

• Sønderby, Ida Elken; Meer, Dennis van der; Moreau, Clara; Kaufmann, Tobias; Walters, G. Bragi & Ellegaard, Maria [Show all 76 contributors for this article] (2021). 1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans. Translational Psychiatry. 11. doi: 10.1038/s41398-021-01213-0. Full text in Research Archive Show summary

  Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers—the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.

• Høgestøl, Einar August; Ghezzo, Samuele; Nygaard, Gro Owren; Espeseth, Thomas; Sowa, Piotr & Beyer, Mona K. [Show all 10 contributors for this article] (2021). Functional connectivity in multiple sclerosis modelled as connectome stability: A 5-year follow-up study. Multiple Sclerosis. ISSN 1352-4585. p. 1–9. doi: 10.1177/13524585211030212. Full text in Research Archive Show summary

  Background: Brain functional connectivity (FC) in multiple sclerosis (MS) is abnormal compared to healthy controls (HCs). More longitudinal studies in MS are needed to evaluate whether FC stability is clinically relevant. Objective: To compare functional magnetic resonance imaging (fMRI)-based FC between MS and HC, and to determine the relationship between longitudinal FC changes and structural brain damage, cognitive performance and physical disability. Methods: T1-weighted MPRAGE and resting-state fMRI (1.5T) were acquired from 70 relapsing-remitting MS patients and 94 matched HC at baseline (mean months since diagnosis 14.0 ± 11) and from 60 MS patients after 5 years. Independent component analysis and network modelling were used to measure longitudinal FC stability and cross-sectional comparisons with HC. Linear mixed models, adjusted for age and sex, were used to calculate correlations. Results: At baseline, patients with MS showed FC abnormalities both within networks and in single connections compared to HC. Longitudinal analyses revealed functional stability and no significant relationships with clinical disability, cognitive performance, lesion or brain volume. Conclusion: FC abnormalities occur already at the first decade of MS, yet we found no relevant clinical correlations for these network deviations. Future large-scale longitudinal fMRI studies across a range of MS subtypes and outcomes are required.

• Bøen, Rune; Ferschmann, Lia; Vijayakumar, Nandita; Øverbye, Knut; Fjell, Anders Martin & Espeseth, Thomas [Show all 7 contributors for this article] (2021). Development of attention networks from childhood to young adulthood: A study of performance, intraindividual variability and cortical thickness. Cortex. ISSN 0010-9452. 138, p. 138–151. doi: 10.1016/j.cortex.2021.01.018. Full text in Research Archive Show summary

  Human cognitive development is manifold, with different functions developing at different speeds at different ages. Attention is an important domain of this cognitive development, and involves distinct developmental trajectories for separate functions, including conflict processing, selection of sensory input and alertness. In children, several studies using the Attention Network Test (ANT) have investigated the development of three attentional networks that carry out the functions of executive control, orienting and alerting. There is, however, a lack of studies on the development of these attentional components across adolescence, limiting our understanding of their protracted development. To fill this knowledge gap, we performed a mixed cross-sectional and longitudinal study using mixed methods to examine the development of the attentional components and their intraindividual variability from late childhood to young adulthood (n = 287, n observations = 408, age range = 8.5–26.7 years, mean follow up interval = 4.4 years). The results indicated that executive control stabilized during late adolescence, while orienting and alerting continued to develop into young adulthood. In addition, a continuous development into young adulthood was observed for the intraindividual variability measures of orienting and alerting. In a subsample with available magnetic resonance imaging (MRI) data (n = 169, n observations = 281), higher alerting scores were associated with thicker cortices within a right prefrontal cortical region and greater age-related cortical thinning in left rolandic operculum, while higher orienting scores were associated with greater age-related cortical thinning in frontal and parietal regions. Finally, increased consistency of orienting performance was associated with thinner cortex in prefrontal regions and reduced age-related thinning in frontal regions.

• Mäki-Marttunen, Verónica & Espeseth, Thomas (2021). Uncovering the locus coeruleus: Comparison of localization methods for functional analysis. NeuroImage. ISSN 1053-8119. 224:117409, p. 1–15. doi: 10.1016/j.neuroimage.2020.117409. Full text in Research Archive
• Sønderby, Ida Elken; Ching, Christopher R. K.; Thomopoulos, Sophia I.; Meer, Dennis van der; Sun, Daqiang & Villalon-Reina, Julio E. [Show all 52 contributors for this article] (2021). Effects of copy number variations on brain structure and risk for psychiatric illness: Large-scale studies from the ENIGMA working groups on CNVs. Human Brain Mapping. ISSN 1065-9471. 43(1), p. 470–499. doi: 10.1002/hbm.25354. Full text in Research Archive Show summary

  The Enhancing NeuroImaging Genetics through Meta-Analysis copy number variant (ENIGMA-CNV) and 22q11.2 Deletion Syndrome Working Groups (22q-ENIGMA WGs) were created to gain insight into the involvement of genetic factors in human brain development and related cognitive, psychiatric and behavioral manifestations. To that end, the ENIGMA-CNV WG has collated CNV and magnetic resonance imaging (MRI) data from ~49,000 individuals across 38 global research sites, yielding one of the largest studies to date on the effects of CNVs on brain structures in the general population. The 22q-ENIGMA WG includes 12 international research centers that assessed over 533 individuals with a confirmed 22q11.2 deletion syndrome, 40 with 22q11.2 duplications, and 333 typically developing controls, creating the largest-ever 22q11.2 CNV neuroimaging data set. In this review, we outline the ENIGMA infrastructure and procedures for multi-site analysis of CNVs and MRI data. So far, ENIGMA has identified effects of the 22q11.2, 16p11.2 distal, 15q11.2, and 1q21.1 distal CNVs on subcortical and cortical brain structures. Each CNV is associated with differences in cognitive, neurodevelopmental and neuropsychiatric traits, with characteristic patterns of brain structural abnormalities. Evidence of gene-dosage effects on distinct brain regions also emerged, providing further insight into genotype–phenotype relationships. Taken together, these results offer a more comprehensive picture of molecular mechanisms involved in typical and atypical brain development. This “genotype-first” approach also contributes to our understanding of the etiopathogenesis of brain disorders. Finally, we outline future directions to better understand effects of CNVs on brain structure and behavior.

• Lam, Max; Chen, Chia-Yen; Ge, Tian; Xia, Yan; Hill, David W. & Trampush, Joey W. [Show all 71 contributors for this article] (2021). Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics. Neuropsychopharmacology. ISSN 0893-133X. 46(10), p. 1788–1801. doi: 10.1038/s41386-021-01023-4. Full text in Research Archive Show summary

  Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify “druggable” targets. Using our meta-analytic data set (N = 373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing.

• 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.

• Mäki-Marttunen, Verónica; Andreassen, Ole Andreas & Espeseth, Thomas (2020). The role of norepinephrine in the pathophysiology of schizophrenia. Neuroscience and Biobehavioral Reviews. ISSN 0149-7634. 118, p. 298–314. doi: 10.1016/j.neubiorev.2020.07.038. Full text in Research Archive Show summary

  Several lines of evidence have suggested for decades a role for norepinephrine (NE) in the pathophysiology and treatment of schizophrenia. Recent experimental findings reveal anatomical and physiological properties of the locus coeruleus-norepinephrine (LC-NE) system and its involvement in brain function and cognition. Here, we integrate these two lines of evidence. First, we review the functional and structural properties of the LC-NE system and its impact on functional brain networks, cognition, and stress, with special emphasis on recent experimental and theoretical advances. Subsequently, we present an update about the role of LC-associated functions for the pathophysiology of schizophrenia, focusing on the cognitive and motivational deficits. We propose that schizophrenia phenomenology, in particular cognitive symptoms, may be explained by an abnormal interaction between genetic susceptibility and stress-initiated LC-NE dysfunction. This in turn, leads to imbalance between LC activity modes, dysfunctional regulation of brain network integration and neural gain, and deficits in cognitive functions. Finally, we suggest how recent development of experimental approaches can be used to characterize LC function in schizophrenia.

• Aminihajibashi, Samira; Hagen, Thomas; Andreassen, Ole Andreas; Laeng, Bruno & Espeseth, Thomas (2020). The effects of cognitive abilities and task demands on tonic and phasic pupil sizes. Biological Psychology. ISSN 0301-0511. 156. doi: 10.1016/j.biopsycho.2020.107945. Full text in Research Archive Show summary

  Previous studies on individual differences in pupil size of healthy individuals and their relation to performance have been inconclusive. Using a novel approach, we tested the effect of general cognitive abilities and level of task performance on pretrial baseline and task-evoked pupil (TEP) sizes (N = 116) while we manipulated the level of task demands using a multiple object tracking task. Results did not reveal an effect of general cognitive abilities, estimated by working memory capacity and gF scores, on either baseline or TEP sizes. In contrast, we found an interaction in TEP sizes between level of overall MOT performance and task demands. We propose that individual differences in TEP sizes are related to state-specific level of task performance and task demands, probably in combination with other factors like age, personality traits, and state-specific level of motivation and arousal. We also suggest methodological confounds that may cause the previous inconclusive findings.

• Aminihajibashi, Samira; Hagen, Thomas; Laeng, Bruno & Espeseth, Thomas (2020). Pupillary and behavioral markers of alerting and orienting: An individual difference approach. Brain and Cognition. ISSN 0278-2626. 143. doi: 10.1016/j.bandc.2020.105597. Full text in Research Archive Show summary

  Measuring task-evoked pupillary (TEP) responses as an index of phasic activity in the locus coeruleus (LC), we examined two competing hypotheses regarding the alerting and orienting mechanisms of attention. According to a dual mechanism account (Fernandez-Duque & Posner, 1997), two separate noradrenergic and cholinergic mechanisms modulate, respectively, the alerting and orienting effects. However, Corbetta and colleagues (2008) proposed that LC phasic activity may also be involved in orienting effect through its functional relationship with the ventral attentional network. We recruited seventy-five healthy Norwegian participants to perform a Posner cueing task. Both behavioral and pupillary responses revealed the alerting effect. Also, both behavioral and pupillary responses indicated that cued attention is affected by age. Behavioral responses also revealed orienting effect However, we found no TEP differences between valid, invalid, and neutral conditions, suggesting that TEP effects were driven by the alerting effect of cue presentation. Moreover, both behavioral and pupillary estimates of alertness and orienting were uncorrelated. Finally, individual differences in general cognitive abilities did not appear to affect the orienting and alerting mechanisms. This pattern of results is consistent with the dual mechanism account of attention. However, the LC involvement in the (re)orienting attention may be driven by state-specific factors.

• Elvsåshagen, Torbjørn; Bahrami, Shahram; Meer, Dennis van der; Agartz, Ingrid; Alnæs, Dag & Barch, Deanna M. [Show all 76 contributors for this article] (2020). The genetic architecture of human brainstem structures and their involvement in common brain disorders. Nature Communications. 11. doi: 10.1038/s41467-020-17376-1. Full text in Research Archive Show summary

  Brainstem regions support vital bodily functions, yet their genetic architectures and involvement in common brain disorders remain understudied. Here, using imaging-genetics data from a discovery sample of 27,034 individuals, we identify 45 brainstem-associated genetic loci, including the first linked to midbrain, pons, and medulla oblongata volumes, and map them to 305 genes. In a replication sample of 7432 participants most of the loci show the same effect direction and are significant at a nominal threshold. We detect genetic overlap between brainstem volumes and eight psychiatric and neurological disorders. In additional clinical data from 5062 individuals with common brain disorders and 11,257 healthy controls, we observe differential volume alterations in schizophrenia, bipolar disorder, multiple sclerosis, mild cognitive impairment, dementia, and Parkinson’s disease, supporting the relevance of brainstem regions and their genetic architectures in common brain disorders.

• Aminihajibashi, Samira; Hagen, Thomas; Foldal, Maja Dyhre; Laeng, Bruno & Espeseth, Thomas (2019). Individual differences in resting-state pupil size: Evidence for association between working memory capacity and pupil size variability. International Journal of Psychophysiology. ISSN 0167-8760. 140, p. 1–7. doi: 10.1016/j.ijpsycho.2019.03.007. Full text in Research Archive Show summary

  Dynamic non-luminance-mediated changes in pupil diameter have frequently been shown to be a reliable index for the level of arousal, mental effort, and activity in the locus coeruleus, the brainstem's noradrenergic arousal center. While pupillometry has most commonly been used to assess the level of arousal in particular psychological states or the level of engagement in cognitive tasks, some recent studies have found a relationship between average resting-state (i.e. baseline) pupil sizes and individuals' working memory capacity (WMC), indicating that individuals with higher WMC on average have larger pupils than individuals with relatively lower WMC. In the present study, we measured pupil size continuously in 212 participants during rest (i.e. while fixating) and estimated WMC in all participants by administering the Letter-Number Sequencing (LNS) task from WAIS-III. We were unable to replicate the relation between average pupil size and WMC. However, the novel finding was that higher WMC was associated with higher variability in resting-state pupil size. The present results are relevant for the current debate on the role of noradrenergic activity on working memory capacity.

• Mäki-Marttunen, Verónica; Hagen, Thomas & Espeseth, Thomas (2019). Proactive and reactive modes of cognitive control can operate independently and simultaneously. Acta Psychologica. ISSN 0001-6918. 199, p. 102891–102891. doi: 10.1016/j.actpsy.2019.102891. Full text in Research Archive
• Lam, Max; Hill, W. David; Trampush, Joey W.; Yu, Jin; Knowles, Emma & Davies, Gail [Show all 68 contributors for this article] (2019). Pleiotropic meta-analysis of cognition, education, and schizophrenia differentiates roles of early neurodevelopmental and adult synaptic pathways. American Journal of Human Genetics. ISSN 0002-9297. 105(2), p. 334–350. doi: 10.1016/j.ajhg.2019.06.012. Full text in Research Archive Show summary

  Susceptibility to schizophrenia is inversely correlated with general cognitive ability at both the phenotypic and the genetic level. Paradoxically, a modest but consistent positive genetic correlation has been reported between schizophrenia and educational attainment, despite the strong positive genetic correlation between cognitive ability and educational attainment. Here we leverage published genome-wide association studies (GWASs) in cognitive ability, education, and schizophrenia to parse biological mechanisms underlying these results. Association analysis based on subsets (ASSET), a pleiotropic meta-analytic technique, allowed jointly associated loci to be identified and characterized. Specifically, we identified subsets of variants associated in the expected (“concordant”) direction across all three phenotypes (i.e., greater risk for schizophrenia, lower cognitive ability, and lower educational attainment); these were contrasted with variants that demonstrated the counterintuitive (“discordant”) relationship between education and schizophrenia (i.e., greater risk for schizophrenia and higher educational attainment). ASSET analysis revealed 235 independent loci associated with cognitive ability, education, and/or schizophrenia at p < 5 × 10−8. Pleiotropic analysis successfully identified more than 100 loci that were not significant in the input GWASs. Many of these have been validated by larger, more recent single-phenotype GWASs. Leveraging the joint genetic correlations of cognitive ability, education, and schizophrenia, we were able to dissociate two distinct biological mechanisms—early neurodevelopmental pathways that characterize concordant allelic variation and adulthood synaptic pruning pathways—that were linked to the paradoxical positive genetic association between education and schizophrenia. Furthermore, genetic correlation analyses revealed that these mechanisms contribute not only to the etiopathogenesis of schizophrenia but also to the broader biological dimensions implicated in both general health outcomes and psychiatric illness.

• Mäki-Marttunen, Verónica; Hagen, Thomas; Laeng, Bruno & Espeseth, Thomas (2019). Distinct Neural Mechanisms Meet Challenges in Dynamic Visual Attention due to Either Load or Object Spacing. Journal of Cognitive Neuroscience. ISSN 0898-929X. 32(1), p. 65–84. doi: 10.1162/jocn_a_01469. Full text in Research Archive
• Richards, Alexander L.; Pardiñas, Antonio F.; Frizzati, Aura; Tansey, Katherine E.; Lynham, Amy J. & Holmans, Peter [Show all 48 contributors for this article] (2019). The Relationship Between Polygenic Risk Scores and Cognition in Schizophrenia. Schizophrenia Bulletin. ISSN 0586-7614. doi: 10.1093/schbul/sbz061. Full text in Research Archive Show summary

  BACKGROUND: Cognitive impairment is a clinically important feature of schizophrenia. Polygenic risk score (PRS) methods have demonstrated genetic overlap between schizophrenia, bipolar disorder (BD), major depressive disorder (MDD), educational attainment (EA), and IQ, but very few studies have examined associations between these PRS and cognitive phenotypes within schizophrenia cases. METHODS: We combined genetic and cognitive data in 3034 schizophrenia cases from 11 samples using the general intelligence factor g as the primary measure of cognition. We used linear regression to examine the association between cognition and PRS for EA, IQ, schizophrenia, BD, and MDD. The results were then meta-analyzed across all samples. A genome-wide association studies (GWAS) of cognition was conducted in schizophrenia cases. RESULTS: PRS for both population IQ (P = 4.39 x 10-28) and EA (P = 1.27 x 10-26) were positively correlated with cognition in those with schizophrenia. In contrast, there was no association between cognition in schizophrenia cases and PRS for schizophrenia (P = .39), BD (P = .51), or MDD (P = .49). No individual variant approached genome-wide significance in the GWAS. CONCLUSIONS: Cognition in schizophrenia cases is more strongly associated with PRS that index cognitive traits in the general population than PRS for neuropsychiatric disorders. This suggests the mechanisms of cognitive variation within schizophrenia are at least partly independent from those that predispose to schizophrenia diagnosis itself. Our findings indicate that this cognitive variation arises at least in part due to genetic factors shared with cognitive performance in populations and is not solely due to illness or treatment-related factors, although our findings are consistent with important contributions from these factors.

• Mäki-Marttunen, Verónica; Hagen, Thomas & Espeseth, Thomas (2019). Task context load induces reactive cognitive control: An fMRI study on cortical and brain stem activity. Cognitive, Affective, & Behavioral Neuroscience. ISSN 1530-7026. p. 1–21. doi: 10.3758/s13415-019-00691-6. Full text in Research Archive Show summary

  When solving dynamic visuo-spatial tasks, the brain copes with perceptual and cognitive processing challenges. In the multiple-object tracking (MOT) task, the number of objects to be tracked (i.e. load) imposes attentional demands, but so does spatial interference from irrelevant objects (i.e. crowding). Presently, it is not clear whether load and crowding activate separate cognitive and physiological mechanisms. Such knowledge would be important to understand the neurophysiology of visual attention. Furthermore, it would help resolve conflicting views between theories of visual cognition, particularly concerning sources of capacity limitations. To address this problem, we varied the degree of processing challenge in the MOT task in two ways: First, the number of objects to track, and second, the spatial proximity between targets and distractors. We first measured task-induced pupil dilations and saccades during MOT. In a separate cohort we measured fMRI brain activity during MOT. The behavioral results in both cohorts revealed that increased load and crowding led to reduced accuracy in an additive manner. Load was associated with pupil dilations, whereas crowding was not. Activity in dorsal attentional areas and frequency of saccades were proportionally larger both with higher levels of load and crowding. Higher crowding recruited additionally ventral attentional areas that may reflect orienting mechanisms. The activity in the brainstem nuclei ventral tegmental area/substantia nigra and locus coeruleus showed clearly dissociated patterns. Our results constitute convergent evidence from independent samples that processing challenges due to load and object spacing may rely on different mechanisms.

• Kaufmann, Tobias; Meer, Dennis van der; Doan, Nhat Trung; Schwarz, Emanuel; Lund, Martina Jonette & Agartz, Ingrid [Show all 84 contributors for this article] (2019). Common brain disorders are associated with heritable patterns of apparent aging of the brain. Nature Neuroscience. ISSN 1097-6256. 22(10), p. 1617–1623. doi: 10.1038/s41593-019-0471-7. Full text in Research Archive Show summary

  Common risk factors for psychiatric and other brain disorders are likely to converge on biological pathways influencing the development and maintenance of brain structure and function across life. Using structural MRI data from 45,615 individuals aged 3–96 years, we demonstrate distinct patterns of apparent brain aging in several brain disorders and reveal genetic pleiotropy between apparent brain aging in healthy individuals and common brain disorders.

• Meer, Dennis van der; Sønderby, Ida Elken; Kaufmann, Tobias; Walters, G. Bragi; Abdellaoui, Abdel & Ames, David [Show all 132 contributors for this article] (2019). Association of copy number variation of the 15q11.2 BP1-BP2 region with cortical and subcortical morphology and cognition. JAMA psychiatry. ISSN 2168-6238. doi: 10.1001/jamapsychiatry.2019.3779. Full text in Research Archive Show summary

  IMPORTANCE: Recurrent microdeletions and duplications in the genomic region 15q11.2 between breakpoints 1 (BP1) and 2 (BP2) are associated with neurodevelopmental disorders. These structural variants are present in 0.5% to 1.0% of the population, making 15q11.2 BP1-BP2 the site of the most prevalent known pathogenic copy number variation (CNV). It is unknown to what extent this CNV influences brain structure and affects cognitive abilities. OBJECTIVE: To determine the association of the 15q11.2 BP1-BP2 deletion and duplication CNVs with cortical and subcortical brain morphology and cognitive task performance. DESIGN, SETTING, AND PARTICIPANTS: In this genetic association study, T1-weighted brain magnetic resonance imaging were combined with genetic data from the ENIGMA-CNV consortium and the UK Biobank, with a replication cohort from Iceland. In total, 203 deletion carriers, 45 247 noncarriers, and 306 duplication carriers were included. Data were collected from August 2015 to April 2019, and data were analyzed from September 2018 to September 2019. MAIN OUTCOMES AND MEASURES: The associations of the CNV with global and regional measures of surface area and cortical thickness as well as subcortical volumes were investigated, correcting for age, age2 , sex, scanner, and intracranial volume. Additionally, measures of cognitive ability were analyzed in the full UK Biobank cohort. RESULTS: Of 45 756 included individuals, the mean (SD) age was 55.8 (18.3) years, and 23 754 (51.9%) were female. Compared with noncarriers, deletion carriers had a lower surface area (Cohen d = −0.41; SE, 0.08; P = 4.9 × 10−8), thicker cortex (Cohen d = 0.36; SE, 0.07; P = 1.3 × 10−7), and a smaller nucleus accumbens (Cohen d = −0.27; SE, 0.07; P = 7.3 × 10−5). There was also a significant negative dose response on cortical thickness (β = −0.24; SE, 0.05; P = 6.8 × 10−7). Regional cortical analyses showed a localization of the effects to the frontal, cingulate, and parietal lobes. Further, cognitive ability was lower for deletion carriers compared with noncarriers on 5 of 7 tasks. CONCLUSIONS AND RELEVANCE: These findings, from the largest CNV neuroimaging study to date, provide evidence that 15q11.2 BP1-BP2 structural variation is associated with brain morphology and cognition, with deletion carriers being particularly affected. The pattern of results fits with known molecular functions of genes in the 15q11.2 BP1-BP2 region and suggests involvement of these genes in neuronal plasticity. These neurobiological effects likely contribute to the association of this CNV with neurodevelopmental disorders

• Satizabal, Claudia L.; Adams, Hieab H.H.; Hibar, Derrek; White, Charles C.; Knol, Maria J. & Stein, Jason L. [Show all 289 contributors for this article] (2019). Genetic architecture of subcortical brain structures in 38,851 individuals. Nature Genetics. ISSN 1061-4036. 51, p. 1624–1636. doi: 10.1038/s41588-019-0511-y. Full text in Research Archive Show summary

  Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

• Walle, Kjersti Mæhlum; Nordvik, Jan Egil; Becker, Frank; Espeseth, Thomas; Sneve, Markus Handal & Laeng, Bruno (2019). Unilateral neglect post stroke: Eye movement frequencies indicate directional hypokinesia while fixation distributions suggest compensational mechanism. Brain and Behavior. 9:e01170(1). doi: 10.1002/brb3.1170. Full text in Research Archive Show summary

  Introduction: Eye movements and spatial attention are closely related, and eye‐tracking can provide valuable information in research on visual attention. We investigated the pathology of overt attention in right hemisphere (RH) stroke patients differing in their severity of neglect symptoms by using eye‐tracking during a dynamic attention task. Methods: Eye movements were recorded in 26 RH stroke patients (13 with and 13 without unilateral spatial neglect, and a matched group of 26 healthy controls during a Multiple Object Tracking task. We assessed the frequency and spatial distributions of fixations, as well as frequencies of eye movements to the left and to the right side of visual space so as to investigate individuals’ efficiency of visual processing, distribution of attentional processing resources, and oculomotoric orienting mechanisms. Results: Both patient groups showed increased fixation frequencies compared to controls. A spatial bias was found in neglect patients’ fixation distribution, depending on neglect severity (indexed by scores on the Behavioral Inattention Test). Patients with more severe neglect had more fixations within the right field, while patients with less severe neglect had more fixations within their left field. Eye movement frequencies were dependent on direction in the neglect patient group, as they made more eye movements toward the right than toward the left. Conclusion: The patient groups’ higher fixation rates suggest that patients are generally less efficient in visual processing. The spatial bias in fixation distribution, dependent on neglect severity, suggested that patients with less severe neglect were able to use compensational mechanisms in their contralesional space. The observed relation between eye movement rates and directions observed in neglect patients provides a measure of the degree of difficulty these patients may encounter during dynamic situations in daily life and supports the idea that directional oculomotor hypokinesia may be a relevant component in this syndrome.

• 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.

• Walle, Kjersti Mæhlum; Nordvik, Jan Egil; Espeseth, Thomas; Becker, Frank & Laeng, Bruno (2018). Multiple object tracking and pupillometry reveal deficits in both selective and intensive attention in unilateral spatial neglect. Journal of Clinical and Experimental Neuropsychology. ISSN 1380-3395. 49(3), p. 270–289. doi: 10.1080/13803395.2018.1536735. Full text in Research Archive
• Fan, Chun Chieh; Schork, Andrew J.; Brown, Timothy T.; Spencer, Barbara E.; Akshoomoff, Natacha & Chen, Chi-Hua [Show all 16 contributors for this article] (2018). Williams Syndrome neuroanatomical score associates with GTF2IRD1 in large-scale magnetic resonance imaging cohorts: A proof of concept for multivariate endophenotypes. Translational Psychiatry. 8:114(1), p. 1–8. doi: 10.1038/s41398-018-0166-y. Full text in Research Archive Show summary

  Despite great interest in using magnetic resonance imaging (MRI) for studying the effects of genes on brain structure in humans, current approaches have focused almost entirely on predefined regions of interest and had limited success. Here, we used multivariate methods to define a single neuroanatomical score of how William’s Syndrome (WS) brains deviate structurally from controls. The score is trained and validated on measures of T1 structural brain imaging in two WS cohorts (training, n = 38; validating, n = 60). We then associated this score with single nucleotide polymorphisms (SNPs) in the WS hemi-deleted region in five cohorts of neurologically and psychiatrically typical individuals (healthy European descendants, n = 1863). Among 110 SNPs within the 7q11.23 WS chromosomal region, we found one associated locus (p = 5e–5) located at GTF2IRD1, which has been implicated in animal models of WS. Furthermore, the genetic signals of neuroanatomical scores are highly enriched locally in the 7q11.23 compared with summary statistics based on regions of interest, such as hippocampal volumes (n = 12,596), and also globally (SNP-heritability = 0.82, se = 0.25, p = 5e−4). The role of genetic variability in GTF2IRD1 during neurodevelopment extends to healthy subjects. Our approach of learning MRI-derived phenotypes from clinical populations with well-established brain abnormalities characterized by known genetic lesions may be a powerful alternative to traditional region of interest-based studies for identifying genetic variants regulating typical brain development.

• Savage, Jeanne E.; Jansen, Philip R.; Stringer, Sven; Watanabe, Kyoko; Bryois, Julien & Leeuw, Christiaan A. de [Show all 117 contributors for this article] (2018). Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence. Nature Genetics. ISSN 1061-4036. 50, p. 912–919. doi: 10.1038/s41588-018-0152-6. Full text in Research Archive
• Mäki-Marttunen, Verónica; Hagen, Thomas; Aminihajibashi, Samira; Foldal, Maja Dyhre; Stavrinou, Maria & Halvorsen, Jens [Show all 8 contributors for this article] (2018). Ocular signatures of proactive versus reactive cognitive control in young adults. Cognitive, Affective, & Behavioral Neuroscience. ISSN 1530-7026. p. 1–15. doi: 10.3758/s13415-018-0621-5. Full text in Research Archive
• Anttila, Verneri; Bulik-Sullivan, Brendan; Finucane, Hilary K.; Walters, Raymond K.; Bras, Jose & Duncan, Laramie [Show all 571 contributors for this article] (2018). Analysis of shared heritability in common disorders of the brain. Science. ISSN 0036-8075. 360(6395). doi: 10.1126/science.aap8757. Full text in Research Archive
• 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.

• Meer, Dennis van der; Rokicki, Jaroslav; Kaufmann, Tobias; Palomera, Aldo Còrdova; Moberget, Torgeir & Alnæs, Dag [Show all 54 contributors for this article] (2018). Brain scans from 21,297 individuals reveal the genetic architecture of hippocampal subfield volumes. Molecular Psychiatry. ISSN 1359-4184. p. 1–13. doi: 10.1038/s41380-018-0262-7. Full text in Research Archive Show summary

  The hippocampus is a heterogeneous structure, comprising histologically distinguishable subfields. These subfields are differentially involved in memory consolidation, spatial navigation and pattern separation, complex functions often impaired in individuals with brain disorders characterized by reduced hippocampal volume, including Alzheimer’s disease (AD) and schizophrenia. Given the structural and functional heterogeneity of the hippocampal formation, we sought to characterize the subfields’ genetic architecture. T1-weighted brain scans (n = 21,297, 16 cohorts) were processed with the hippocampal subfields algorithm in FreeSurfer v6.0. We ran a genome-wide association analysis on each subfield, co-varying for whole hippocampal volume. We further calculated the single-nucleotide polymorphism (SNP)-based heritability of 12 subfields, as well as their genetic correlation with each other, with other structural brain features and with AD and schizophrenia. All outcome measures were corrected for age, sex and intracranial volume. We found 15 unique genome-wide significant loci across six subfields, of which eight had not been previously linked to the hippocampus. Top SNPs were mapped to genes associated with neuronal differentiation, locomotor behaviour, schizophrenia and AD. The volumes of all the subfields were estimated to be heritable (h2 from 0.14 to 0.27, all p < 1 × 10–16) and clustered together based on their genetic correlations compared with other structural brain features. There was also evidence of genetic overlap of subicular subfield volumes with schizophrenia. We conclude that hippocampal subfields have partly distinct genetic determinants associated with specific biological processes and traits. Taking into account this specificity may increase our understanding of hippocampal neurobiology and associated pathologies.

• Hagen, Thomas; Espeseth, Thomas & Laeng, Bruno (2018). Chasing Animals With Split Attention: Are Animals Prioritized in Visual Tracking? i-Perception. 9(5), p. 1–35. doi: 10.1177/2041669518795932. Full text in Research Archive Show summary

  Some evolutionary psychologists have hypothesized that animals have priority in human attention. That is, they should be detected and selected more efficiently than other types of objects, especially man-made ones. Such a priority mechanism should automatically deploy more attentional resources and dynamic monitoring toward animal stimuli than nonanimals. Consequently, we postulated that variations of the multiple object or identity tracking and multiple event monitoring tasks should be particularly suitable paradigms for addressing the animate monitoring hypothesis, given their dynamic properties and dependency on divided attention. We used images of animals and artifacts and found neither a substantial sign of improvement in tracking the positions associated with animal stimuli nor a significant distracting effect of animals. We also failed to observe a significant prioritization in orders of response for positions associated with animals. While we observed an advantage for animals in event monitoring, this appeared to be dependent on properties of the task, as confirmed in further experiments. Moreover, we observed a small but inconclusive advantage for animals in identity accuracy. Thus, under certain conditions, some bias toward animals could be observed, but the evidence was weak and inconclusive. To conclude, effect sizes were generally small and not conclusively in favor of the expected attentional bias for animals. We found moderate to strong evidence that images of animals do not improve positional tracking, do not act as more effective distractors, are not selected prior to artifacts in the response phase, and are not easier to monitor for changes in size.

• Davies, Gail; Lam, Max; Harris, Sarah E.; Trampush, Joey W.; Luciano, Michelle & Hill, W. David [Show all 221 contributors for this article] (2018). Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function. Nature Communications. 9(2098), p. 1–16. doi: 10.1038/s41467-018-04362-x. Full text in Research Archive Show summary

  General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16–102) and find 148 genome-wide significant independent loci (P < 5 × 10−8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.

• 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
• Polushina, Tatiana; Giddaluru, Sudheer; Bettella, Francesco; Espeseth, Thomas; Lundervold, Astri & Djurovic, Srdjan [Show all 12 contributors for this article] (2017). Analysis of the joint effect of SNPs to identify independent loci and allelic heterogeneity in schizophrenia GWAS data. Translational Psychiatry. 7(12). doi: 10.1038/s41398-017-0033-2. Full text in Research Archive
• Lam, Max; Trampush, Joey W.; Yu, Jin; Knowles, Emma; Davies, Gail & Liewald, David C. [Show all 65 contributors for this article] (2017). Large-scale cognitive GWAS meta-analysis reveals tissue-specific neural expression and potential nootropic drug targets. Cell reports. 21(9), p. 2597–2613. doi: 10.1016/j.celrep.2017.11.028. Full text in Research Archive
• Hibar, Derrek; Adams, Hieab H.H.; Jahanshad, Neda; Chauhan, Ganesh; Stein, Jason L. & Hofer, Edith [Show all 332 contributors for this article] (2017). Novel genetic loci associated with hippocampal volume. Nature Communications. 8:13624, p. 1–12. doi: 10.1038/ncomms13624. Full text in Research Archive Show summary

  The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer’s disease (rg=−0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.

• Trampush, Joey W.; Yang, M.L.Z.; Yu, Jin; Knowles, Emma; Davies, Gail & Liewald, David C.M. [Show all 66 contributors for this article] (2017). GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report form the COGENT consortium. Molecular Psychiatry. ISSN 1359-4184. 22(3), p. 336–345. doi: 10.1038/mp.2016.244. Full text in Research Archive Show summary

  The complex nature of human cognition has resulted in cognitive genomics lagging behind many other fields in terms of gene discovery using genome-wide association study (GWAS) methods. In an attempt to overcome these barriers, the current study utilized GWAS meta-analysis to examine the association of common genetic variation (~8M single-nucleotide polymorphisms (SNP) with minor allele frequency ⩾1%) to general cognitive function in a sample of 35 298 healthy individuals of European ancestry across 24 cohorts in the Cognitive Genomics Consortium (COGENT). In addition, we utilized individual SNP lookups and polygenic score analyses to identify genetic overlap with other relevant neurobehavioral phenotypes. Our primary GWAS meta-analysis identified two novel SNP loci (top SNPs: rs76114856 in the CENPO gene on chromosome 2 and rs6669072 near LOC105378853 on chromosome 1) associated with cognitive performance at the genome-wide significance level (P<5 × 10^−8). Gene-based analysis identified an additional three Bonferroni-corrected significant loci at chromosomes 17q21.31, 17p13.1 and 1p13.3. Altogether, common variation across the genome resulted in a conservatively estimated SNP heritability of 21.5% (s.e.=0.01%) for general cognitive function. Integration with prior GWAS of cognitive performance and educational attainment yielded several additional significant loci. Finally, we found robust polygenic correlations between cognitive performance and educational attainment, several psychiatric disorders, birth length/weight and smoking behavior, as well as a novel genetic association to the personality trait of openness. These data provide new insight into the genetics of neurocognitive function with relevance to understanding the pathophysiology of neuropsychiatric illness.

• Li, Dong; Chang, Xiao; Connolly, John J.; Tian, Lifeng; Liu, Yichuan & Bhoj, Elizabeth J. [Show all 198 contributors for this article] (2017). A genome-wide association study of anorexia nervosa suggests a risk locus implicated in dysregulated leptin signaling. Scientific Reports. 7:3847, p. 1–9. doi: 10.1038/s41598-017-01674-8. Full text in Research Archive
• Lillenes, Meryl Sønderby; Støen, Mari; Günther, Clara-Cecilie; Selnes, Per; Stenset, Vidar & Espeseth, Thomas [Show all 9 contributors for this article] (2017). Mitochondrial transcription factor A (TFAM) rs1937 and AP endonuclease 1 (APE1) rs1130409 alleles are associated with reduced cognitive performance. Neuroscience Letters. ISSN 0304-3940. 645, p. 46–52. doi: 10.1016/j.neulet.2017.02.062. Full text in Research Archive Show summary

  Mitochondrial dysfunction and DNA damage is intimately connected to ageing and neurodegeneration, including Alzheimer’s disease (AD). A particular culprit in this context is oxidative stress, which is a result of increased reactive oxygen species (ROS) due to hyperactive or dysfunctional mitochondria and/or reduced DNA repair capacity. Base excision repair (BER) is the major pathway for repairing oxidative damage events in chromosomal and mitochondrial DNA. Defects in BER have been detected in ageing and neurodegeneration. Mitochondrial transcription factor A (TFAM) plays an important role in the maintenance of mitochondrial DNA integrity. The present study investigated single nucleotide polymorphisms (SNPs) in the genes encoding the BER components MutYH, OGG1, APE1, PolB and PolG and the gene encoding mitochondrial TFAM in a cohort of 161 AD patients, 96 non-AD patient controls (PC) and 192 healthy controls (HC). Notably, the minor allele carriers of APE1 rs1130409 and the common allele carriers of TFAM rs1937 were associated with reduced mini-mental state examination score in AD patients, PC and HC, with no distinction of SNP frequencies in either of these sub-groups. Collectively, the results suggest an association between DNA maintenance and decline in cognitive function. These studies enlighten the normal brain aging process and point to potential new biomarkers for cognitive function and impairment.

• Athanasiu, Lavinia; Giddaluru, Sudheer; Neto, Carla Patricia Duarte Fernande; Christoforou, Andrea; Reinvang, Ivar & Lundervold, Astri [Show all 17 contributors for this article] (2017). A genetic association study of CSMD1 and CSMD2 with cognitive function. Brain, Behavior, and Immunity. ISSN 0889-1591. 61, p. 209–216. doi: 10.1016/j.bbi.2016.11.026. Full text in Research Archive
• Maretty, Lasse; Jensen, Jacob Malte; Petersen, Bent; Sibbesen, Jonas Andreas; Liu, Siyang & Villesen, Palle [Show all 59 contributors for this article] (2017). Sequencing and de novo assembly of 150 genomes from Denmark as a population reference. Nature. ISSN 0028-0836. 548(7665), p. 87–91. doi: 10.1038/nature23264. Full text in Research Archive
• Jensen, Jacob Malte; Villesen, Palle; Friborg, Rune Møllegaard; Espeseth, Thomas; Hellard, Stephanie Le & Mailund, Thomas [Show all 8 contributors for this article] (2017). Assembly and analysis of 100 full MHC haplotypes from the Danish population. Genome Research. ISSN 1088-9051. 27(9), p. 1597–1607. doi: 10.1101/gr.218891.116. Full text in Research Archive
• Qian, Peng; Schork, Andrew J.; Bartsch, Hauke; Lo, Min-Tzu; Panizzon, Matthew S. & Westlye, Lars Tjelta [Show all 20 contributors for this article] (2016). Conservation of Distinct Genetically-Mediated Human Cortical Pattern. PLoS Genetics. ISSN 1553-7390. 12:e1006143(7). doi: 10.1371/journal.pgen.1006143. Full text in Research Archive Show summary

  The many subcomponents of the human cortex are known to follow an anatomical pattern and functional relationship that appears to be highly conserved between individuals. This suggests that this pattern and the relationship among cortical regions are important for cortical function and likely shaped by genetic factors, although the degree to which genetic factors contribute to this pattern is unknown. We assessed the genetic relationships among 12 cortical surface areas using brain images and genotype information on 2,364 unrelated individuals, brain images on 466 twin pairs, and transcriptome data on 6 postmortem brains in order to determine whether a consistent and biologically meaningful pattern could be identified from these very different data sets. We find that the patterns revealed by each data set are highly consistent (p<10−3), and are biologically meaningful on several fronts. For example, close genetic relationships are seen in cortical regions within the same lobes and, the frontal lobe, a region showing great evolutionary expansion and functional complexity, has the most distant genetic relationship with other lobes. The frontal lobe also exhibits the most distinct expression pattern relative to the other regions, implicating a number of genes with known functions mediating immune and related processes. Our analyses reflect one of the first attempts to provide an assessment of the biological consistency of a genetic phenomenon involving the brain that leverages very different types of data, and therefore is not just statistical replication which purposefully use very similar data sets.

• Guadalupe, Tulio; Mathias, Samuel R.; VanErp, Theo G.M.; Whelan, Christopher D.; Zwiers, Marcel P. & Abe, Yoshinari [Show all 161 contributors for this article] (2016). Human subcortical brain asymmetries in 15,847 people worldwide reveal effects of age and sex. Brain Imaging and Behavior. ISSN 1931-7557. Published ahead of print, p. 1–18. doi: 10.1007/s11682-016-9629-z. Full text in Research Archive
• Adams, Hieab H.H.; Hibar, Derrek; Chouraki, Vincent; Stein, Jason L.; Nyquist, Paul A. & Renteriá, Miguel E. [Show all 342 contributors for this article] (2016). Novel genetic loci underlying human intracranial volume identified through genome-wide association. Nature Neuroscience. ISSN 1097-6256. 19(12), p. 1569–1582. doi: 10.1038/nn.4398. Full text in Research Archive
• Giddaluru, Sudheer; Espeseth, Thomas; Salami, Alireza; Westlye, Lars Tjelta; Lundquist, Anders & Christoforou, Andrea [Show all 13 contributors for this article] (2016). Genetics of structural connectivity and information processing in the brain. Brain Structure and Function. ISSN 1863-2653. 221(9), p. 4643–4661. doi: 10.1007/s00429-016-1194-0. Full text in Research Archive
• Gunnarsson, Bjarni; Jonsdottir, Gudrun A; Bjornsdottir, Gyda; Konte, Bettina; Sulem, Patrick & Kristmundsdottir, Snædis [Show all 31 contributors for this article] (2016). A sequence variant associating with educational attainment also affects childhood cognition. Scientific Reports. 6. doi: 10.1038/srep36189. Full text in Research Archive
• Athanasiadis, Georgios; Cheng, Jade Y.; Vilhjálmsson, Bjarni J.; Jørgensen, Frank G.; Als, Thomas D. & Hellard, Stephanie Le [Show all 12 contributors for this article] (2016). Nationwide genomic study in Denmark reveals remarkable population homogeneity. Genetics. ISSN 0016-6731. 204(2), p. 711–722. doi: 10.1534/genetics.116.189241. Full text in Research Archive
• Howrigan, Dave; Simonson, M.A.; Davies, Gail; Harris, SE; Tenesa, A. & Starr, JM [Show all 47 contributors for this article] (2016). Genome-wide autozygosity is associated with lower general cognitive ability. Molecular Psychiatry. ISSN 1359-4184. 21(6), p. 837–843. doi: 10.1038/mp.2015.120. Full text in Research Archive
• Davies, Gail; Armstrong, N; Bis, JC; Bressler, J; Chouraki, V & Giddaluru, Sudheer [Show all 129 contributors for this article] (2015). Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949). Molecular Psychiatry. ISSN 1359-4184. 20(2), p. 183–192. doi: 10.1038/mp.2014.188. Full text in Research Archive Show summary

  General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53 949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10−9, MIR2113; rs17522122, P=2.55 × 10−8, AKAP6; rs10119, P=5.67 × 10−9, APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10−6). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10−17). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer’s disease: TOMM40, APOE, ABCG1 and MEF2C.

• Myrum, Craig; Giddaluru, Sudheer; Jacobsen, Kaya Kvarme; Espeseth, Thomas; Nyberg, Lars & Lundervold, Astri [Show all 14 contributors for this article] (2015). Common variants in the ARC gene are not associated with cognitive abilities. Brain and Behavior. 5(10). doi: 10.1002/brb3.376. Full text in Research Archive Show summary

  Introduction: The Activity-Regulated Cytoskeleton-associated (ARC) gene encodes a protein that is critical for the consolidation of synaptic plasticity and long-term memory formation. Given ARC's key role in synaptic plasticity, we hypothesized that genetic variations in ARC may contribute to interindividual variability in human cognitive abilities or to attention-deficit hyperactivity disorder (ADHD) susceptibility, where cognitive impairment often accompanies the disorder. Methods: We tested whether ARC variants are associated with six measures of cognitive functioning in 670 healthy subjects in the Norwegian Cognitive NeuroGenetics (NCNG) by extracting data from its Genome-Wide Association Study (GWAS). In addition, the Swedish Betula sample of 1800 healthy subjects who underwent similar cognitive testing was also tested for association with 19 tag SNPs. Results: No ARC variants show association at the study-wide level, but several markers show a trend toward association with human cognitive functions. We also tested for association between ARC SNPs and ADHD in a Norwegian sample of cases and controls, but found no significant associations. Conclusion: This study suggests that common genetic variants located in ARC do not account for variance in human cognitive abilities, though small effects cannot be ruled out.

• Wehling, Eike; Lundervold, Astri; Espeseth, Thomas; Reinvang, Ivar; Brämerson, Annika & Nordin, Steven (2015). Even cognitively well-functioning adults are unaware of their olfactory dysfunction: Implications for ENT clinicians and researchers. Rhinology. ISSN 0300-0729. 53(1), p. 89–94. doi: 10.4193/Rhino14.081. Full text in Research Archive
• Hansell, Narelle K.; Halford, Graeme S.; Andrews, Glenda; Shum, David H.K.; Harris, Sarah E. & Davies, Gail [Show all 25 contributors for this article] (2015). Genetic basis of a cognitive complexity metric. PLOS ONE. 10:e0123886(4). doi: 10.1371/journal.pone.0123886. Full text in Research Archive
• Chen, Chi-Hua; Peng, Qian; Schork, Andrew J.; Lo, Min-Tzu; Fan, Chun-Chieh & Wang, Yunpeng [Show all 22 contributors for this article] (2015). Large-scale genomics unveil polygenic architecture of human cortical surface area. Nature Communications. 6:7549. doi: 10.1038/ncomms8549. Full text in Research Archive Show summary

  Little is known about how genetic variation contributes to neuroanatomical variability, and whether particular genomic regions comprising genes or evolutionarily conserved elements are enriched for effects that influence brain morphology. Here, we examine brain imaging and single-nucleotide polymorphisms (SNPs) data from B2,700 individuals. We show that a substantial proportion of variation in cortical surface area is explained by additive effects of SNPs dispersed throughout the genome, with a larger heritable effect for visual and auditory sensory and insular cortices (h2B0.45). Genome-wide SNPs collectively account for, on average, about half of twin heritability across cortical regions (N¼466 twins). We find enriched genetic effects in or near genes. We also observe that SNPs in evolutionarily more conserved regions contributed significantly to the heritability of cortical surface area, particularly, for medial and temporal cortical regions. SNPs in less conserved regions contributed more to occipital and dorsolateral prefrontal cortices.

• Trampush, Joey W.; Lencz, Todd; Knowles, Emma; Davies, Gail; Guha, Saurav & Pe'er, Itsik [Show all 53 contributors for this article] (2015). Independent evidence for an association between general cognitive ability and a genetic locus for educational attainment. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics. ISSN 1552-4841. 168(5), p. 363–373. doi: 10.1002/ajmg.b.32319. Full text in Research Archive
• Tesli, Martin Steen; Kauppi, Karolina; Bettella, Franscesco; Brandt, Christine Lycke; Kaufmann, Tobias & Espeseth, Thomas [Show all 12 contributors for this article] (2015). Altered brain activation during emotional face processing in relation to both diagnosis and polygenic risk of bipolar disorder. PLOS ONE. 10:e0134202(7). doi: 10.1371/journal.pone.0134202. Full text in Research Archive Show summary

  Objectives Bipolar disorder (BD) is a highly heritable disorder with polygenic inheritance. Among the most consistent findings from functional magnetic imaging (fMRI) studies are limbic hyperactivation and dorsal hypoactivation. However, the relation between reported brain functional abnormalities and underlying genetic risk remains elusive. This is the first cross-sectional study applying a whole-brain explorative approach to investigate potential influence of BD case-control status and polygenic risk on brain activation. Methods A BD polygenic risk score (PGRS) was estimated from the Psychiatric Genomics Consortium BD case-control study, and assigned to each individual in our independent sample (N=85 BD cases and 121 healthy controls (HC)), all of whom participated in an fMRI emotional faces matching paradigm. Potential differences in BOLD response across diagnostic groups were explored at whole-brain level in addition to amygdala as a region of interest. Putative effects of BD PGRS on brain activation were also investigated. Results At whole-brain level, BD cases presented with significantly lower cuneus/precuneus activation than HC during negative face processing (Z-threshold=2.3 as cluster-level correction). The PGRS was associated positively with increased right inferior frontal gyrus (rIFG) activation during negative face processing. For amygdala activation, there were no correlations with diagnostic status or PGRS. Conclusions These findings are in line with previous reports of reduced precuneus and altered rIFG activation in BD. While these results demonstrate the ability of PGRS to reveal underlying genetic risk of altered brain activation in BD, the lack of convergence of effects at diagnostic and PGRS level suggests that this relation is a complex one.

• Fjell, Anders Martin; Westlye, Lars Tjelta; Amlien, Inge; Tamnes, Christian Krog; Grydeland, Håkon & Engvig, Andreas [Show all 11 contributors for this article] (2015). High-expanding cortical regions in human development and evolution are related to higher intellectual abilities. Cerebral Cortex. ISSN 1047-3211. 25, p. 26–34. doi: 10.1093/cercor/bht201. Full text in Research Archive Show summary

  Cortical surface area has tremendously expanded during human evolution, and similar patterns of cortical expansion have been observed during childhood development. An intriguing hypothesis is that the high-expanding cortical regions also show the strongest correlations with intellectual function in humans. However, we do not know how the regional distribution of correlations between intellectual function and cortical area maps onto expansion in development and evolution. Here, in a sample of 1048 participants, we show that regions in which cortical area correlates with visuospatial reasoning abilities are generally high expanding in both development and evolution. Several regions in the frontal cortex, especially the anterior cingulate, showed high expansion in both development and evolution. The area of these regions was related to intellectual functions in humans. Low-expanding areas were not related to cognitive scores. These findings suggest that cortical regions involved in higher intellectual functions have expanded the most during development and evolution. The radial unit hypothesis provides a common framework for interpretation of the findings in the context of evolution and prenatal development, while additional cellular mechanisms, such as synaptogenesis, gliogenesis, dendritic arborization, and intracortical myelination, likely impact area expansion in later childhood. This is a pre-copyedited, author-produced PDF of an article accepted for publication in Cerebral Cortex following peer review. The version of record [insert complete citation information here] is available online at: http://dx.doi.org/10.1093/cercor/bht201

• Kauppi, Karolina; Westlye, Lars Tjelta; Tesli, Martin Steen; Bettella, Franscesco; Brandt, Christine Lycke & Mattingsdal, Morten [Show all 12 contributors for this article] (2015). Polygenic risk for schizophrenia associated with working memory-related prefrontal brain activation in patients with schizophrenia and healthy controls. Schizophrenia Bulletin. ISSN 0586-7614. 41(3), p. 736–743. doi: 10.1093/schbul/sbu152. Full text in Research Archive Show summary

  Schizophrenia is a highly heritable and polygenic disease, and identified common genetic variants have shown weak individual effects. Many studies have reported altered working memory (WM)-related brain activation in schizophrenia, preferentially in the frontal lobe. Such differences in brain activations could reflect inherited alterations possibly involved in the disease etiology, or rather secondary disease-related mechanisms. The use of polygenic risk scores (PGRS) based on a large number of risk polymorphisms with small effects is a valuable approach to examine the effect of cumulative genetic risk on brain functioning. This study examined the impact of cumulative genetic risk for schizophrenia on WM-related brain activations, assessed with functional magnetic resonance imaging. For each participant (63 schizophrenia patients and 118 healthy controls), we calculated a PGRS for schizophrenia based on 18 862 single-nucleotide polymorphism in a large multicenter genome-wide association study including 9146 schizophrenia patients and 12 111 controls, performed by the Psychiatric Genomics Consortium. As expected, the PGRS was significantly higher in patients compared with healthy controls. Further, the PGRS was related to differences in frontal lobe brain activation between high and low WM demand. Specifically, even in absence of main effects of diagnosis, increased PGRS was associated with decreased activation difference in the right middle-superior prefrontal cortex (BA 10/11) and the right inferior frontal gyrus (BA 45). This effect was seen in both cases and controls, and was not influenced by sex, age, or task performance. The findings support the notion of dysregulation of frontal lobe functioning as an inherited vulnerability factor in schizophrenia.

• Hibar, Derrek; Stein, Jason L; Renteria, Miguel E; Arias-Vasquez, Alejandro; Desrivieres, Sylvane & Jahanshad, Neda [Show all 287 contributors for this article] (2015). Common genetic variants influence human subcortical brain structures. Nature. ISSN 0028-0836. 520(7546), p. 224–229. doi: 10.1038/nature14101. Full text in Research Archive
• Espeseth, Thomas (2015). Visuell oppmerksomhet sett fra et matematisk og genetisk perspektiv. Nevropsykologi : Medlemsblad for Norsk Nevropsykologisk Forening. ISSN 1500-8347. 17(1), p. 14–23. Full text in Research Archive
• Hill, Wayne David; Davies, Gail; Lagemaat, Louie N. Van De; Christoforou, Andrea; Marioni, Riccardo R. & Fernandes, Carla Duarte [Show all 27 contributors for this article] (2014). Human cognitive ability is influenced by genetic variation in components of postsynaptic signalling complexes assembled by NMDA receptors and MAGUK proteins. Translational Psychiatry. 4:e341. doi: 10.1038/tp.2013.114. Full text in Research Archive Show summary

  Differences in general cognitive ability (intelligence) account for approximately half of the variation in any large battery of cognitive tests and are predictive of important life events including health. Genome-wide analyses of common single-nucleotide polymorphisms indicate that they jointly tag between a quarter and a half of the variance in intelligence. However, no single polymorphism has been reliably associated with variation in intelligence. It remains possible that these many small effects might be aggregated in networks of functionally linked genes. Here, we tested a network of 1461 genes in the postsynaptic density and associated complexes for an enriched association with intelligence. These were ascertained in 3511 individuals (the Cognitive Ageing Genetics in England and Scotland (CAGES) consortium) phenotyped for general cognitive ability, fluid cognitive ability, crystallised cognitive ability, memory and speed of processing. By analysing the results of a genome wide association study (GWAS) using Gene Set Enrichment Analysis, a significant enrichment was found for fluid cognitive ability for the proteins found in the complexes of N-methyl-D-aspartate receptor complex; P=0.002. Replication was sought in two additional cohorts (N=670 and 2062). A meta-analytic P-value of 0.003 was found when these were combined with the CAGES consortium. The results suggest that genetic variation in the macromolecular machines formed by membrane-associated guanylate kinase (MAGUK) scaffold proteins and their interaction partners contributes to variation in intelligence.

• Fernandes, Carla Duarte; Westlye, Lars Tjelta; Giddaluru, Sudheer; Christoforou, Andrea; Kauppi, Karolina & Adolfsson, Rolf [Show all 13 contributors for this article] (2014). Lack of association of the rs1344706 ZNF804A variant with cognitive functions and DTI indices of white matter microstructure in two independent healthy populations. Psychiatry Research : Neuroimaging. ISSN 0925-4927. 222(1-2), p. 60–66. doi: 10.1016/j.pscychresns.2014.02.009. Full text in Research Archive
• Fjell, Anders Martin; Westlye, Lars Tjelta; Grydeland, Håkon; Amlien, Inge; Espeseth, Thomas & Reinvang, Ivar [Show all 9 contributors for this article] (2014). Accelerating cortical thinning: Unique to dementia or universal in aging? Cerebral Cortex. ISSN 1047-3211. 24(4), p. 919–934. doi: 10.1093/cercor/bhs379. Full text in Research Archive
• Tesli, Martin Steen; Espeseth, Thomas; Bettella, Franscesco; Mattingsdal, Morten; Aas, Monica & Melle, Ingrid [Show all 8 contributors for this article] (2014). Polygenic risk score and the psychosis continuum model. Acta Psychiatrica Scandinavica. ISSN 0001-690X. 130(4), p. 311–317. doi: 10.1111/acps.12307. Full text in Research Archive
• Walhovd, Kristine B; Fjell, Anders Martin & Espeseth, Thomas (2014). Cognitive decline and brain pathology in aging - need for a dimensional, lifespan and systems vulnerability view. Scandinavian Journal of Psychology. ISSN 0036-5564. 55(3), p. 244–254. doi: 10.1111/sjop.12120. Full text in Research Archive Show summary

  Changes in brain structure and activity as well as cognitive function are commonly seen in aging. However, it is not known when aging of brain and cognition starts, and how much of the changes observed in seemingly healthy older adults that can be ascribed to incipient neurodegenerative disease. Recent research has yielded evidence that the borders between development and aging sometimes can be fuzzy, as can the borders between dementing disease and normal age changes. In this review, we argue that many factors affecting cognitive decline and dementia represents quantitative rather than qualitative differences in characteristics that commonly exist in the population. Further, factors known to affect brain and cognition in aging will often do so through a life-long accumulation of impact, and does not need to be specific to aging. And finally, a host of environmental and genetic factors and their interplay determine optimal aging, leaving room for potential for environmental interventions to affect the outcome of the aging process. Together, we argue that these factors call for a dimensional rather than categorical, lifespan rather than aging, and multidimensional systems-vulnerability rather than simple “hypothetical biomarker” model of age-associated cognitive decline and dementia. This has implications for how we should view lifespan trajectories of change in brain and cognitive function, and how we can study, prevent, diagnose and treat age-associated cognitive deficits. This is the peer reviewed version of the article, which has been published in final form at http://dx.doi.org/10.1111/sjop.12120. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.

• Greenwood, Pamela M.; Espeseth, Thomas; Lin, Ming-Kuan; Reinvang, Ivar & Parasuraman, Raja (2014). Longitudinal change in working memory as a function of APOE genotype in midlife and old age. Scandinavian Journal of Psychology. ISSN 0036-5564. 55(3), p. 268–277. doi: 10.1111/sjop.12123. Full text in Research Archive
• Christoforou, Andrea; Espeseth, Thomas; Davies, Gail L.; Fernandes, Carla Duarte; Giddaluru, Sudheer & Mattheisen, Manuel [Show all 24 contributors for this article] (2014). GWAS-based pathway analysis differentiates between fluid and crystallized intelligence. Genes, Brain and Behavior. ISSN 1601-1848. 13(7). doi: 10.1111/gbb.12152. Full text in Research Archive Show summary

  Cognitive abilities vary among people. About 40–50% of this variability is due to general intelligence (g), which reflects the positive correlation among individuals' scores on diverse cognitive ability tests. g is positively correlated with many life outcomes, such as education, occupational status and health, motivating the investigation of its underlying biology. In psychometric research, a distinction is made between general fluid intelligence (gF) – the ability to reason in novel situations – and general crystallized intelligence (gC) – the ability to apply acquired knowledge. This distinction is supported by developmental and cognitive neuroscience studies. Classical epidemiological studies and recent genome-wide association studies (GWASs) have established that these cognitive traits have a large genetic component. However, no robust genetic associations have been published thus far due largely to the known polygenic nature of these traits and insufficient sample sizes. Here, using two GWAS datasets, in which the polygenicity of gF and gC traits was previously confirmed, a gene- and pathway-based approach was undertaken with the aim of characterizing and differentiating their genetic architecture. Pathway analysis, using genes selected on the basis of relaxed criteria, revealed notable differences between these two traits. gF appeared to be characterized by genes affecting the quantity and quality of neurons and therefore neuronal efficiency, whereas long-term depression (LTD) seemed to underlie gC. Thus, this study supports the gF–gC distinction at the genetic level and identifies functional annotations and pathways worthy of further investigation.

• Reichborn-Kjennerud, Ted; Knudsen, Gun Peggy; Andreassen, Ole Andreas; Espeseth, Thomas; Lundervold, Astri & Reinvang, Ivar [Show all 50 contributors for this article] (2014). A genome-wide association study of anorexia nervosa. Molecular Psychiatry. ISSN 1359-4184. 19(10), p. 1085–1094. doi: 10.1038/mp.2013.187. Full text in Research Archive Show summary

  Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21 080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge–purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01 × 10−7) in SOX2OT and rs17030795 (P=5.84 × 10−6) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76 × 10−6) between CUL3 and FAM124B and rs1886797 (P=8.05 × 10−6) near SPATA13. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4 × 10−6), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field.

• Lencz, T; Knowles, Emily; Davies, G; Guha, S; Liewald, DC & Starr, JM [Show all 46 contributors for this article] (2014). Molecular genetic evidence for overlap between general cognitive ability and risk for schizophrenia: A report from the Cognitive Genomics consorTium (COGENT). Molecular Psychiatry. ISSN 1359-4184. 19(2), p. 168–174. doi: 10.1038/mp.2013.166. Full text in Research Archive Show summary

  It has long been recognized that generalized deficits in cognitive ability represent a core component of schizophrenia (SCZ), evident before full illness onset and independent of medication. The possibility of genetic overlap between risk for SCZ and cognitive phenotypes has been suggested by the presence of cognitive deficits in first-degree relatives of patients with SCZ; however, until recently, molecular genetic approaches to test this overlap have been lacking. Within the last few years, large-scale genome-wide association studies (GWAS) of SCZ have demonstrated that a substantial proportion of the heritability of the disorder is explained by a polygenic component consisting of many common single-nucleotide polymorphisms (SNPs) of extremely small effect. Similar results have been reported in GWAS of general cognitive ability. The primary aim of the present study is to provide the first molecular genetic test of the classic endophenotype hypothesis, which states that alleles associated with reduced cognitive ability should also serve to increase risk for SCZ. We tested the endophenotype hypothesis by applying polygenic SNP scores derived from a large-scale cognitive GWAS meta-analysis (~5000 individuals from nine nonclinical cohorts comprising the Cognitive Genomics consorTium (COGENT)) to four SCZ case-control cohorts. As predicted, cases had significantly lower cognitive polygenic scores compared to controls. In parallel, polygenic risk scores for SCZ were associated with lower general cognitive ability. In addition, using our large cognitive meta-analytic data set, we identified nominally significant cognitive associations for several SNPs that have previously been robustly associated with SCZ susceptibility. Results provide molecular confirmation of the genetic overlap between SCZ and general cognitive ability, and may provide additional insight into pathophysiology of the disorder.

• Espeseth, Thomas; Vangkilde, Signe A; Petersen, Anders; Dyrholm, Mads & Westlye, Lars Tjelta (2014). TVA-based assessment of attentional capacities-associations with age and indices of brain white matter microstructure. Frontiers in Psychology. 5. doi: 10.3389/fpsyg.2014.01177. Full text in Research Archive Show summary

  In this study the primary aims were to characterize the effects of age on basic components of visual attention derived from assessments based on a theory of visual attention (TVA) in 325 healthy volunteers covering the adult lifespan (19-81 years). Furthermore, we aimed to investigate how age-related differences on TVA parameters are associated with white matter (WM) microstructure as indexed by diffusion tensor imaging (DTI). Finally, we explored how TVA parameter estimates were associated with complex, or multicomponent indices of processing speed (Digit-symbol substitution, DSS) and fluid intelligence (gF). The results indicated that the TVA parameters for visual short-term memory capacity, K, and for attentional selectivity, α, were most strongly associated with age before the age of 50. However, in this age range, it was the parameter for processing speed, C, that was most clearly associated with DTI indices, in this case fractional anisotropy (FA), particularly in the genu and body of the corpus callosum. Furthermore, differences in the C parameter partially mediated differences in DSS within this age range. After the age of 50, the TVA parameter for the perceptual threshold, t 0, as well as K, were most strongly related to participant age. Both parameters, but t 0 more strongly so than K, were associated WM diffusivity, particularly in projection fibers such as the internal capsule, the sagittal stratum, and the corona radiata. Within this age range, t 0 partially mediated age-related differences in gF. The results are consistent with, and provide novel empirical support for the neuroanatomical localization of TVA computations as outlined in the neuronal interpretation of TVA (NTVA). Furthermore, the results indicate that to understand the biological sources of age-related changes in processing speed and fluid cognition, it may be useful to employ methods that allow for computational fractionation of these multicomponent measures.

• Thompson, Paul M; Stein, Jason L; Medland, Sarah E; Hibar, Derrek P; Vasquez, Alejandro Arias & Renteria, Miguel E [Show all 289 contributors for this article] (2014). The ENIGMA Consortium: Large-scale collaborative analyses of neuroimaging and genetic data. Brain Imaging and Behavior. ISSN 1931-7557. 8(2), p. 153–182. doi: 10.1007/s11682-013-9269-5. Full text in Research Archive Show summary

  The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA’s first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.

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• Herrebrøden, Henrik; Espeseth, Thomas & Bishop, Laura (2023). Cognitive load affects effort, performance, and kinematics in elite and non-elite rowers. Journal of Sport & Exercise Psychology (JSEP). ISSN 0895-2779. 45(S1), p. S83–S83. doi: 10.1123/jsep.2023-0077. Full text in Research Archive Show summary

  The extent to which elite athletes depend on mental effort and attention to task execution has been a debated topic. Some studies have suggested that motor experts might be relatively unaffected in the face of distraction and that they might even perform better when they attend to extraneous cognitive stimuli (for example in a dual-task paradigm), as compared to single-task conditions where they concentrate fully on a sports task. However, task complexity and participants’ skill levels have so far been relatively modest in most dual-task studies. To address gaps in past research, a multi-method study was conducted using a rowing ergometer task. Participants were nine male elite rowers from the Norwegian national rowing team, preparing for the 2020 Olympic Games in Tokyo, as well as nine male recreational rowers. Participants engaged in three-minute rowing trials of varying task demands, including single-task conditions (focusing on rowing only) and dual-task conditions (focusing on rowing and solving arithmetic problems). Performance and mental effort were measured via ergometer data (i.e., rowing speed values) and eye-tracking measures (i.e., blink rates and pupil size measurements), respectively. Movement kinematics was measured by motion capture technology. The results suggested that adding extraneous cognitive load led to performance decline and increased mental effort across all participants. Both elites and non-elites demonstrated kinematic changes when going from single-task to dual-task performance. That is, kinematic events in participants’ lower-body and upper-body segments became more temporally coupled, and more in line with movement patterns associated with novice athletes when the extraneous cognitive load was added. This study contradicts several past findings and suggests that elite athletes rely on attentional resources to execute fundamental aspects of their performance. Funding source: Research Council of Norway.

• Korbmacher, Max; Wang, Meng-yun; Eikeland, Rune; Buchert, Ralph; Andreassen, Ole & Espeseth, Thomas [Show all 10 contributors for this article] (2023). Field strength and potentially scan quality influence brain age estimates. Full text in Research Archive
• Kaufmann, Tobias; Meer, Dennis van der; Doan, Nhat Trung; Schwarz, Emanuel; Lund, Martina Jonette & Agartz, Ingrid [Show all 97 contributors for this article] (2020). Publisher Correction: Common brain disorders are associated with heritable patterns of apparent aging of the brain (Nature Neuroscience, (2019), 22, 10, (1617-1623), 10.1038/s41593-019-0471-7). Nature Neuroscience. ISSN 1097-6256. 23(2), p. 295–295. doi: 10.1038/s41593-019-0553-6. Full text in Research Archive
• Mäki-Marttunen, Verónica; Hagen, Thomas & Espeseth, Thomas (2019). Correction to: Task context load induces reactive cognitive control: An fMRI study on cortical and brain stem activity (Cognitive, Affective, & Behavioral Neuroscience, (2019), 19, 4, (945-965), 10.3758/s13415-019-00691-6). Cognitive, Affective, & Behavioral Neuroscience. ISSN 1530-7026. 19(4), p. 1094–1094. doi: 10.3758/s13415-019-00701-7. Full text in Research Archive
• Foster, Philip P; Baldwin, Carryl L.; Thompson, James Campbell; Espeseth, Thomas; Jiang, Xiong & Greenwood, Pamela M. (2019). Editorial: Cognitive and Brain Aging: Interventions to Promote Well-Being in Old Age. Frontiers in Aging Neuroscience. 11. doi: 10.3389/fnagi.2019.00268. Full text in Research Archive
• Davies, Gail; Lam, Max; Harris, Sarah E.; Trampush, Joey W.; Luciano, Michelle & Hill, W. David [Show all 222 contributors for this article] (2019). Author Correction: Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function (Nature Communications, (2018), 9, 1, (2098), 10.1038/s41467-018-04362-x). Nature Communications. 10(1). doi: 10.1038/s41467-019-10160-w. Full text in Research Archive
• Lam, Max; Trampush, Joey W.; Yu, Jin; Knowles, Emma; Djurovic, Srdjan & Melle, Ingrid [Show all 61 contributors for this article] (2018). Multi-Trait analysis of gwas and biological insights into cognition: A response to Hill (2018). Twin Research and Human Genetics. ISSN 1832-4274. 21(5), p. 394–397. doi: 10.1017/thg.2018.46. Full text in Research Archive
• Stavrinou, Maria; Asko, Olgerta; Hagen, Thomas; Foldal, Maja Dyhre & Espeseth, Thomas (2017). The long term effects of reward on spatial priority maps studied with Electroencephalography and Pupillometry. Full text in Research Archive
• Haász, Judit; Lundervold, Arvid; Espeseth, Thomas; Thomassen, Lars & Specht, Karsten (2014). Longitudinal changes in visual working memory performance and frontoparietal intrinsic connectivity network synchronization non-cortical stroke. Full text in Research Archive

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