1. Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition.
- Author
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van der Meer D, Sønderby IE, Kaufmann T, Walters GB, Abdellaoui A, Ames D, Amunts K, Andersson M, Armstrong NJ, Bernard M, Blackburn NB, Blangero J, Boomsma DI, Brodaty H, Brouwer RM, Bülow R, Cahn W, Calhoun VD, Caspers S, Cavalleri GL, Ching CRK, Cichon S, Ciufolini S, Corvin A, Crespo-Facorro B, Curran JE, Dalvie S, Dazzan P, de Geus EJC, de Zubicaray GI, de Zwarte SMC, Delanty N, den Braber A, Desrivieres S, Di Forti M, Doherty JL, Donohoe G, Ehrlich S, Eising E, Espeseth T, Fisher SE, Fladby T, Frei O, Frouin V, Fukunaga M, Gareau T, Glahn DC, Grabe HJ, Groenewold NA, Gústafsson Ó, Haavik J, Haberg AK, Hashimoto R, Hehir-Kwa JY, Hibar DP, Hillegers MHJ, Hoffmann P, Holleran L, Hottenga JJ, Hulshoff Pol HE, Ikeda M, Jacquemont S, Jahanshad N, Jockwitz C, Johansson S, Jönsson EG, Kikuchi M, Knowles EEM, Kwok JB, Le Hellard S, Linden DEJ, Liu J, Lundervold A, Lundervold AJ, Martin NG, Mather KA, Mathias SR, McMahon KL, McRae AF, Medland SE, Moberget T, Moreau C, Morris DW, Mühleisen TW, Murray RM, Nordvik JE, Nyberg L, Olde Loohuis LM, Ophoff RA, Owen MJ, Paus T, Pausova Z, Peralta JM, Pike B, Prieto C, Quinlan EB, Reinbold CS, Reis Marques T, Rucker JJH, Sachdev PS, Sando SB, Schofield PR, Schork AJ, Schumann G, Shin J, Shumskaya E, Silva AI, Sisodiya SM, Steen VM, Stein DJ, Strike LT, Tamnes CK, Teumer A, Thalamuthu A, Tordesillas-Gutiérrez D, Uhlmann A, Úlfarsson MÖ, van 't Ent D, van den Bree MBM, Vassos E, Wen W, Wittfeld K, Wright MJ, Zayats T, Dale AM, Djurovic S, Agartz I, Westlye LT, Stefánsson H, Stefánsson K, Thompson PM, and Andreassen OA
- Subjects
- Brain Cortical Thickness, Cerebral Cortex diagnostic imaging, Cerebral Cortex physiology, Chromosome Breakpoints, DNA Copy Number Variations physiology, Female, Genetic Association Studies, Heterozygote, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Neuroimaging, Neuropsychological Tests, Organ Size genetics, Cerebral Cortex anatomy & histology, Chromosomes, Human, Pair 15 genetics, Cognition, DNA Copy Number Variations genetics
- 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 (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.
- Published
- 2020
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