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Original Investigation
October 30, 2019

Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition

Writing Committee for the ENIGMA-CNV Working Group
JAMA Psychiatry. Published online October 30, 2019. doi:https://doi.org/10.1001/jamapsychiatry.2019.3779
Key Points

Question  How does the 15q11.2 BP1-BP2 copy number variation affect cortical and subcortical brain morphology and cognitive performance?

Findings  In this genetic association study, using a discovery/replication design with more than 45 000 individuals, a dose response of 15q11.2 BP1-BP2 copy number variations on cortical thickness as well as smaller accumbens and cortical surface area was found for deletion carriers, particularly in frontal brain regions. Further, compared with noncarriers, deletion carriers had poorer cognitive performance.

Meaning  These findings point toward altered brain structure for deletion carriers, implicating aberrant cortical morphology, thereby providing an improved understanding of the association of this copy number variation with neurodevelopmental disorders.


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.

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