Медицинская библиотека · JAMA psychiatry · 2020

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

СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАПеревод пока не подготовлен

Аннотация

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.

Для цитирования: Writing Committee for the ENIGMA-CNV Working Group, van der Meer Dennis, Sønderby Ida E, Kaufmann Tobias, Walters G Bragi, Abdellaoui Abdel, Ames David, Amunts Katrin, Andersson Micael, Armstrong Nicola J, Bernard Manon, Blackburn Nicholas B, Blangero John, Boomsma Dorret I, Brodaty Henry, Brouwer Rachel M, Bülow Robin, Cahn Wiepke, Calhoun Vince D, Caspers Svenja, Cavalleri Gianpiero L, Ching Christopher R K, Cichon Sven, Ciufolini Simone, Corvin Aiden, Crespo-Facorro Benedicto, Curran Joanne E, Dalvie Shareefa, Dazzan Paola, de Geus Eco J C, de Zubicaray Greig I, de Zwarte Sonja M C, Delanty Norman, den Braber Anouk, Desrivieres Sylvane, Di Forti Marta, Doherty Joanne L, Donohoe Gary, Ehrlich Stefan, Eising Else, Espeseth Thomas, Fisher Simon E, Fladby Tormod, Frei Oleksandr, Frouin Vincent, Fukunaga Masaki, Gareau Thomas, Glahn David C, Grabe Hans J, Groenewold Nynke A, Gústafsson Ómar, Haavik Jan, Haberg Asta K, Hashimoto Ryota, Hehir-Kwa Jayne Y, Hibar Derrek P, Hillegers Manon H J, Hoffmann Per, Holleran Laurena, Hottenga Jouke-Jan, Hulshoff Pol Hilleke E, Ikeda Masashi, Jacquemont Sébastien, Jahanshad Neda, Jockwitz Christiane, Johansson Stefan, Jönsson Erik G, Kikuchi Masataka, Knowles Emma E M, Kwok John B, Le Hellard Stephanie, Linden David E J, Liu Jingyu, Lundervold Arvid, Lundervold Astri J, Martin Nicholas G, Mather Karen A, Mathias Samuel R, McMahon Katie L, McRae Allan F, Medland Sarah E, Moberget Torgeir, Moreau Clara, Morris Derek W, Mühleisen Thomas W, Murray Robin M, Nordvik Jan E, Nyberg Lars, Olde Loohuis Loes M, Ophoff Roel A, Owen Michael J, Paus Tomas, Pausova Zdenka, Peralta Juan M, Pike Bruce, Prieto Carlos, Quinlan Erin Burke, Reinbold Céline S, Reis Marques Tiago, Rucker James J H, Sachdev Perminder S, Sando Sigrid B, Schofield Peter R, Schork Andrew J, Schumann Gunter, Shin Jean, Shumskaya Elena, Silva Ana I, Sisodiya Sanjay M, Steen Vidar M, Stein Dan J, Strike Lachlan T, Tamnes Christian K, Teumer Alexander, Thalamuthu Anbupalam, Tordesillas-Gutiérrez Diana, Uhlmann Anne, Úlfarsson Magnús Ö, van 't Ent Dennis, van den Bree Marianne B M, Vassos Evangelos, Wen Wei, Wittfeld Katharina, Wright Margaret J, Zayats Tetyana, Dale Anders M, Djurovic Srdjan, Agartz Ingrid, Westlye Lars T, Stefánsson Hreinn, Stefánsson Kári, Thompson Paul M, Andreassen Ole A. Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition.. JAMA psychiatry. 2020. DOI: 10.1001/jamapsychiatry.2019.3779.

Предметные рубрики MeSH

Brain Cortical Thickness Cerebral Cortex Chromosome Breakpoints Chromosomes, Human, Pair 15 Cognition DNA Copy Number Variations Female Genetic Association Studies Heterozygote Humans Magnetic Resonance Imaging Male Middle Aged Neuroimaging Neuropsychological Tests Organ Size

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