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


ABSTRACT: 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 (??=?-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.

SUBMITTER: Writing Committee for the ENIGMA-CNV Working Group 

PROVIDER: S-EPMC6822096 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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

van der Meer Dennis D   Sønderby Ida E IE   Kaufmann Tobias T   Walters G Bragi GB   Abdellaoui Abdel A   Ames David D   Amunts Katrin K   Andersson Micael M   Armstrong Nicola J NJ   Bernard Manon M   Blackburn Nicholas B NB   Blangero John J   Boomsma Dorret I DI   Brodaty Henry H   Brouwer Rachel M RM   Bülow Robin R   Cahn Wiepke W   Calhoun Vince D VD   Caspers Svenja S   Cavalleri Gianpiero L GL   Ching Christopher R K CRK   Cichon Sven S   Ciufolini Simone S   Corvin Aiden A   Crespo-Facorro Benedicto B   Curran Joanne E JE   Dalvie Shareefa S   Dazzan Paola P   de Geus Eco J C EJC   de Zubicaray Greig I GI   de Zwarte Sonja M C SMC   Delanty Norman N   den Braber Anouk A   Desrivieres Sylvane S   Di Forti Marta M   Doherty Joanne L JL   Donohoe Gary G   Ehrlich Stefan S   Eising Else E   Espeseth Thomas T   Fisher Simon E SE   Fladby Tormod T   Frei Oleksandr O   Frouin Vincent V   Fukunaga Masaki M   Gareau Thomas T   Glahn David C DC   Grabe Hans J HJ   Groenewold Nynke A NA   Gústafsson Ómar Ó   Haavik Jan J   Haberg Asta K AK   Hashimoto Ryota R   Hehir-Kwa Jayne Y JY   Hibar Derrek P DP   Hillegers Manon H J MHJ   Hoffmann Per P   Holleran Laurena L   Hottenga Jouke-Jan JJ   Hulshoff Pol Hilleke E HE   Ikeda Masashi M   Jacquemont Sébastien S   Jahanshad Neda N   Jockwitz Christiane C   Johansson Stefan S   Jönsson Erik G EG   Kikuchi Masataka M   Knowles Emma E M EEM   Kwok John B JB   Le Hellard Stephanie S   Linden David E J DEJ   Liu Jingyu J   Lundervold Arvid A   Lundervold Astri J AJ   Martin Nicholas G NG   Mather Karen A KA   Mathias Samuel R SR   McMahon Katie L KL   McRae Allan F AF   Medland Sarah E SE   Moberget Torgeir T   Moreau Clara C   Morris Derek W DW   Mühleisen Thomas W TW   Murray Robin M RM   Nordvik Jan E JE   Nyberg Lars L   Olde Loohuis Loes M LM   Ophoff Roel A RA   Owen Michael J MJ   Paus Tomas T   Pausova Zdenka Z   Peralta Juan M JM   Pike Bruce B   Prieto Carlos C   Quinlan Erin Burke EB   Reinbold Céline S CS   Reis Marques Tiago T   Rucker James J H JJH   Sachdev Perminder S PS   Sando Sigrid B SB   Schofield Peter R PR   Schork Andrew J AJ   Schumann Gunter G   Shin Jean J   Shumskaya Elena E   Silva Ana I AI   Sisodiya Sanjay M SM   Steen Vidar M VM   Stein Dan J DJ   Strike Lachlan T LT   Tamnes Christian K CK   Teumer Alexander A   Thalamuthu Anbupalam A   Tordesillas-Gutiérrez Diana D   Uhlmann Anne A   Úlfarsson Magnús Ö MÖ   van 't Ent Dennis D   van den Bree Marianne B M MBM   Vassos Evangelos E   Wen Wei W   Wittfeld Katharina K   Wright Margaret J MJ   Zayats Tetyana T   Dale Anders M AM   Djurovic Srdjan S   Agartz Ingrid I   Westlye Lars T LT   Stefánsson Hreinn H   Stefánsson Kári K   Thompson Paul M PM   Andreassen Ole A OA  

JAMA psychiatry 20200401 4


<h4>Importance</h4>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.<h4>Objective</h4>To determine the association of  ...[more]

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