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Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition.
JAMA Psychiatry ( IF 25.8 ) Pub Date : 2020-04-01 , DOI: 10.1001/jamapsychiatry.2019.3779
, Dennis van der Meer 1, 2 , Ida E Sønderby 1 , Tobias Kaufmann 1 , G Bragi Walters 3, 4 , Abdel Abdellaoui 5, 6 , David Ames 7, 8 , Katrin Amunts 9, 10, 11 , Micael Andersson 12, 13 , Nicola J Armstrong 14 , Manon Bernard 15 , Nicholas B Blackburn 16 , John Blangero 16 , Dorret I Boomsma 6, 17, 18 , Henry Brodaty 19, 20 , Rachel M Brouwer 21 , Robin Bülow 22 , Wiepke Cahn 21, 23 , Vince D Calhoun 24, 25 , Svenja Caspers 9, 11, 26 , Gianpiero L Cavalleri 27, 28 , Christopher R K Ching 29, 30 , Sven Cichon 9, 31, 32 , Simone Ciufolini 33 , Aiden Corvin 34 , Benedicto Crespo-Facorro 35, 36 , Joanne E Curran 16 , Shareefa Dalvie 37 , Paola Dazzan 33 , Eco J C de Geus 6, 17, 18 , Greig I de Zubicaray 38 , Sonja M C de Zwarte 21 , Norman Delanty 28, 39 , Anouk den Braber 6, 17, 40 , Sylvane Desrivieres 41 , Marta Di Forti 41 , Joanne L Doherty 42, 43 , Gary Donohoe 44 , Stefan Ehrlich 45 , Else Eising 46 , Thomas Espeseth 47 , Simon E Fisher 46, 48 , Tormod Fladby 49, 50 , Oleksandr Frei 1 , Vincent Frouin 51 , Masaki Fukunaga 52, 53 , Thomas Gareau 51 , David C Glahn 54, 55, 56 , Hans J Grabe 57, 58 , Nynke A Groenewold 37 , Ómar Gústafsson 3 , Jan Haavik 59, 60 , Asta K Haberg 61, 62 , Ryota Hashimoto 63, 64 , Jayne Y Hehir-Kwa 65 , Derrek P Hibar 66 , Manon H J Hillegers 67 , Per Hoffmann 32, 68 , Laurena Holleran 44 , Jouke-Jan Hottenga 6, 17, 18 , Hilleke E Hulshoff Pol 21 , Masashi Ikeda 69 , Sébastien Jacquemont 70, 71 , Neda Jahanshad 30 , Christiane Jockwitz 9, 72 , Stefan Johansson 73, 74 , Erik G Jönsson 1, 75 , Masataka Kikuchi 76 , Emma E M Knowles 54, 56 , John B Kwok 77, 78 , Stephanie Le Hellard 79, 80 , David E J Linden 2, 42 , Jingyu Liu 24 , Arvid Lundervold 59, 81 , Astri J Lundervold 82 , Nicholas G Martin 83 , Karen A Mather 19, 84 , Samuel R Mathias 54, 56 , Katie L McMahon 85 , Allan F McRae 86, 87 , Sarah E Medland 88 , Torgeir Moberget 1 , Clara Moreau 70, 89 , Derek W Morris 44 , Thomas W Mühleisen 9, 10, 31 , Robin M Murray 41 , Jan E Nordvik 90 , Lars Nyberg 12, 13, 91 , Loes M Olde Loohuis 92 , Roel A Ophoff 92 , Michael J Owen 42 , Tomas Paus 93, 94 , Zdenka Pausova 15, 94 , Juan M Peralta 16 , Bruce Pike 95 , Carlos Prieto 96 , Erin Burke Quinlan 97 , Céline S Reinbold 31, 32, 47 , Tiago Reis Marques 33, 98 , James J H Rucker 41 , Perminder S Sachdev 19, 99 , Sigrid B Sando 61, 100 , Peter R Schofield 78, 101 , Andrew J Schork 102 , Gunter Schumann 97 , Jean Shin 15, 94 , Elena Shumskaya 48, 103 , Ana I Silva 43, 104 , Sanjay M Sisodiya 105 , Vidar M Steen 79, 80 , Dan J Stein 37, 106 , Lachlan T Strike 87 , Christian K Tamnes 1, 107, 108 , Alexander Teumer 109 , Anbupalam Thalamuthu 19 , Diana Tordesillas-Gutiérrez 110 , Anne Uhlmann 37 , Magnús Ö Úlfarsson 3, 111 , Dennis van 't Ent 6, 17 , Marianne B M van den Bree 42, 112 , Evangelos Vassos 41, 113 , Wei Wen 19 , Katharina Wittfeld 57, 58 , Margaret J Wright 87 , Tetyana Zayats 59, 114, 115 , Anders M Dale 116 , Srdjan Djurovic 79, 117 , Ingrid Agartz 1, 74, 108 , Lars T Westlye 1, 47 , Hreinn Stefánsson 3 , Kári Stefánsson 3, 4 , Paul M Thompson 30 , Ole A Andreassen 1
Affiliation  

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.

中文翻译:

15q11.2 BP1-BP2 区域的拷贝数变异与皮质和皮质下形态和认知的关联。

重要性 断点 1 (BP1) 和 2 (BP2) 之间基因组区域 15q11.2 中的反复微缺失和重复与神经发育障碍相关。这些结构变异存在于 0.5% 至 1.0% 的人群中,使得 15q11.2 BP1-BP2 成为已知最常见的致病性拷贝数变异 (CNV) 的位点。目前尚不清楚这种 CNV 在多大程度上影响大脑结构和认知能力。目的 确定 15q11.2 BP1-BP2 缺失和重复 CNV 与皮质和皮质下脑形态和认知任务表现的关联。设计、设置和参与者 在这项遗传关联研究中,T1 加权脑磁共振成像与来自 ENIGMA-CNV 联盟和英国生物银行的遗传数据以及来自冰岛的复制队列相结合。总共包括203个缺失携带者、45 247个非携带者和306个重复携带者。数据收集时间为 2015 年 8 月至 2019 年 4 月,数据分析时间为 2018 年 9 月至 2019 年 9 月。 主要结果和措施 研究了 CNV 与全球和区域表面积、皮质厚度以及皮质下体积测量值之间的关联,修正了年龄、年龄2、性别、扫描仪和颅内容积。此外,还对整个英国生物银行队列的认知能力测量进行了分析。结果 45 756 名受试者中,平均 (SD) 年龄为 55.8 (18.3) 岁,其中 23 754 名 (51.9%) 为女性。与非携带者相比,缺失携带者的表面积较低(Cohen d = -0.41;SE,0.08;P = 4.9 × 10-8),皮质较厚(Cohen d = 0.36;SE,0.07;P = 1.3 × 10-7) )和较小的伏隔核(Cohen d = -0.27;SE,0.07;P = 7.3 × 10-5)。皮质厚度也存在显着的负剂量反应(β = -0.24;SE,0.05;P = 6.8 × 10-7)。区域皮层分析显示,影响仅限于额叶、扣带皮层和顶叶。此外,与非携带者相比,缺失携带者在 7 项任务中有 5 项的认知能力较低。结论和相关性 这些来自迄今为止最大的 CNV 神经影像研究的发现提供了证据,表明 15q11.2 BP1-BP2 结构变异与大脑形态和认知相关,其中缺失携带者尤其受到影响。结果模式符合 15q11.2 BP1-BP2 区域基因的已知分子功能,表明这些基因参与神经元可塑性。这些神经生物学效应可能导致这种 CNV 与神经发育障碍的关联。
更新日期:2020-04-01
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