Effects of eight neuropsychiatric copy number variants on human brain structure
Authors: Modenato Claudia , Kumar Kuldeep , Moreau Clara , Martin-Brevet Sandra , Huguet Guillaume , Schramm Catherine , Jean-Louis Martineau , Martin Charles-Olivier , Younis Nadine , Tamer Petra , Douard Elise , Thébault-Dagher Fanny , Côté Valérie , Charlebois Audrey-Rose , Deguire Florence , Maillard Anne M. , Rodriguez-Herreros Borja , Pain Aurèlie , Richetin Sonia ,   16p11.2 European Consortium, Addor Marie-Claude , Andrieux Joris , Arveiler Benoît , Baujat Geneviève , Sloan-Béna Frédérique , Belfiore Marco , Bonneau Dominique , Bouquillon Sonia , Boute Odile , Brusco Alfredo , Busa Tiffany , Caberg Jean- Hubert , Campion Dominique , Colombert Vanessa , Cordier Marie-Pierre , David Albert , Debray François-Guillaume , Delrue Marie-Ange , Doco-Fenzy Martine , Dunkhase-Heinl Ulrike , Edery Patrick , Fagerberg Christina , Faivre Laurence , Forzano Francesca , Genevieve David , Gérard Marion , Giachino Daniela , Guichet Agnès , Guillin Olivier , Héron Delphine , Isidor Bertrand , Jacquette Aurélia , Jaillard Sylvie , Journel Hubert , Keren Boris , Lacombe Didier , Lebon Sébastien , Le Caignec Cédric , Lemaître Marie-Pierre , Lespinasse James , Mathieu-Dramart Michèle , Mercier Sandra , Mignot Cyril , Missirian Chantal , Petit Florence , Pilekær Sørensen Kristina , Pinson Lucile , Plessis Ghislaine , Prieur Fabienne , Raymond Alexandre , Rooryck-Thambo Caroline , Rossi Massimiliano , Sanlaville Damien , Schlott Kristiansen Britta , Schluth-Bolard Caroline , Till Marianne , Van Haelst Mieke , Van Maldergem Lionel ,   Simons Searchlight Consortium, Alupay Hanalore , Aaronson Benjamin , Ackerman Sean , Ankenman Katy , Anwar Ayesha , Atwell Constance , Bowe Alexandra , Beaudet Arthur L. , Benedetti Marta , Berg Jessica , Berman Jeffrey , Berry Leandra N. , Bibb Audrey L. , Blaskey Lisa , Brennan Jonathan , Brewton Christie M. , Buckner Randy , Bukshpun Polina , Burko Jordan , Cali Phil , Cerban Bettina , Chang Yishin , Cheong Maxwell , Chow Vivian , Chu Zili , Chudnovskaya Darina , Cornew Lauren , Dale Corby , Dell John , Dempsey Allison G. , Deschamps Trent , Earl Rachel , Edgar James , Elgin Jenna , Olson Jennifer Endre , Evans Yolanda L. , Findlay Anne , Fischbach Gerald D. , Fisk Charlie , Fregeau Brieana , Gaetz Bill , Gaetz Leah , Garza Silvia , Gerdts Jennifer , Glenn Orit , Gobuty Sarah E. , Golembski Rachel , Greenup Marion , Heiken Kory , Hines Katherine , Hinkley Leighton , Jackson Frank I. , Jenkins Julian , Jeremy Rita J. , Johnson Kelly , Kanne Stephen M. , Kessler Sudha , Khan Sarah Y. , Ku Matthew , Kuschner Emily , Laakman Anna L. , Lam Peter , Lasala Morgan W. , Lee Hana , LaGuerre Kevin , Levy Susan , Cavanagh Alyss Lian , Llorens Ashlie V. , Campe Katherine Loftus , Luks Tracy L. , Marco Elysa J. , Martin Stephen , Martin Alastair J. , Marzano Gabriela , Masson Christina , McGovern Kathleen E. , Keehn Rebecca McNally , Miller David T. , Miller Fiona K. , Moss Timothy J. , Murray Rebecca , Nagarajan Srikantan S. , Nowell Kerri P. , Owen Julia , Paal Andrea M. , Packer Alan , Page Patricia Z. , Paul Brianna M. , Peters Alana , Peterson Danica , Poduri Annapurna , Pojman Nicholas J. , Porche Ken , Proud Monica B. , Qasmieh Saba , Ramocki Melissa B. , Reilly Beau , Roberts Timothy P. L. , Shaw Dennis , Sinha Tuhin , Smith-Packard Bethanny , Gallagher Anne Snow , Swarnakar Vivek , Thieu Tony , Triantafallou Christina , Vaughan Roger , Wakahiro Mari , Wallace Arianne , Ward Tracey , Wenegrat Julia , Wolken Anne , Melie-Garcia Lester , Kushan Leila , Silva Ana I. , van den Bree Marianne B. M. , Linden David E. J. , Owen Michael J. , Hall Jeremy , Lippé Sarah , Chakravarty Mallar , Bzdok Danilo , Bearden Carrie E. , Draganski Bogdan , Jacquemont Sébastien 
Published: July 2021

Many copy number variants (CNVs) confer risk for the same range of neurodevelopmental symptoms and psychiatric conditions including autism and schizophrenia. Yet, to date neuroimaging studies have typically been carried out one mutation at a time, showing that CNVs have large effects on brain anatomy. Here, we aimed to characterize and quantify the distinct brain morphometry effects and latent dimensions across 8 neuropsychiatric CNVs. We analyzed T1-weighted MRI data from clinically and non-clinically ascertained CNV carriers (deletion/duplication) at the 1q21.1 (n = 39/28), 16p11.2 (n = 87/78), 22q11.2 (n = 75/30), and 15q11.2 (n = 72/76) loci as well as 1296 non-carriers (controls). Case-control contrasts of all examined genomic loci demonstrated effects on brain anatomy, with deletions and duplications showing mirror effects at the global and regional levels. Although CNVs mainly showed distinct brain patterns, principal component analysis (PCA) loaded subsets of CNVs on two latent brain dimensions, which explained 32 and 29% of the variance of the 8 Cohen’s d maps. The cingulate gyrus, insula, supplementary motor cortex, and cerebellum were identified by PCA and multi-view pattern learning as top regions contributing to latent dimension shared across subsets of CNVs. The large proportion of distinct CNV effects on brain morphology may explain the small neuroimaging effect sizes reported in polygenic psychiatric conditions. Nevertheless, latent gene brain morphology dimensions will help subgroup the rapidly expanding landscape of neuropsychiatric variants and dissect the heterogeneity of idiopathic conditions.