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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