Clara A. Moreau, Annabelle Harvey, Kuldeep Kumar, Guillaume Huguet, Sebastian G.W. Urchs, Elise A. Douard, Laura M. Schultz, Hanad Sharmarke, Khadije Jizi, Charles-Olivier Martin, Nadine Younis, Petra Tamer, Thomas Rolland, Jean-Louis Martineau, Pierre Orban, Ana Isabel Silva, Jeremy Hall, Marianne B.M. van den Bree, Michael J. Owen, David E.J. Linden, Aurelie Labbe, Sarah Lippé, Carrie E. Bearden, Laura Almasy, David C. Glahn, Paul M. Thompson, Thomas Bourgeron, Pierre Bellec, Sebastien Jacquemont, RS: MHeNs - R2 - Mental Health, Psychiatry 1, RS: MHeNs School for Mental Health and Neuroscience, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, School for Mental Health & Neuroscience, RS: MHeNs - R3 - Neuroscience, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre de recherche du CHU Sainte-Justine / Research Center of the Sainte-Justine University Hospital [Montreal, Canada], Université de Montréal (UdeM)-CHU Sainte Justine [Montréal], Centre de Recherche de l'Institut Universitaire de Gériatrie de Montréal (CRIUGM), Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], Children’s Hospital of Philadelphia (CHOP ), Centre de Recherche de l’Institut Universitaire en Santé Mentale de Montréal (CRIUSMM), Université de Montréal (UdeM), Cardiff University, Maastricht University [Maastricht], HEC Montréal (HEC Montréal), Semel Institute for Neuroscience and Human Behavior [Los Angeles, Ca], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), University of Pennsylvania, Harvard Medical School [Boston] (HMS), Boston Children's Hospital, Centre de recherche de l'Institut universitaire de gériatrie de Montreal (CRIUGM), and This research was supported by Compute Canada (ID 3037 and gsf-624), the Brain Canada Multi investigator research initiative (MIRI), Canada First Research Excellence Fund, Institute of Data Valorization, Healthy Brain Healthy Lives (Dr. Jacquemont). Dr. Jacquemont is a recipient of a Canada Research Chair in neurodevelopmental disorders, and a chair from the Jeanne et Jean Louis Levesque Foundation. This work was supported by a grant from the Brain Canada Multi-Investigator initiative (Dr. Jacquemont) and a grant from The Canadian Institutes of Health Research (CIHR 400528, Dr. Jacquemont). Clara Moreau and Thomas Bourgeron are supported by AIMS-2-TRIALS - which received support from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 777394. The Cardiff CNV cohort was supported by the Wellcome Trust Strategic Award 'DEFINE' and the National Centre for Mental Health with funds from Health and Care Research Wales (code 100202/Z/12/Z). Data from the UCLA cohort provided by Dr. Bearden (participants with 22q11.2 deletions or duplications and controls) was supported through grants from the NIH (U54EB020403), NIMH (R01MH085953, R01MH100900, 1U01MH119736, R21MH116473 ), and the Simons Foundation (SFARI Explorer Award). Finally, data from another study were obtained through the OpenFMRI project (http://openfmri.org) from the Consortium for Neuropsychiatric Phenomics (CNP), which was supported by NIH Roadmap for Medical Research grants UL1-DE019580, RL1MH083268, RL1MH083269, RL1DA024853, RL1MH083270, RL1LM009833, PL1MH083271, and PL1NS062410. Dr P. Bellec is a fellow ('Chercheur boursier Junior 2') of the 'Fonds de recherche du Québec - Santé', Data preprocessing and analyses were supported in part by the Courtois foundation (Dr Bellec). This work was supported by Simons Foundation Grant Nos. SFARI219193 and SFARI274424. We thank all of the families at the participating Simons Variation in Individuals Project (VIP) sites, as well as the Simons VIP Consortium. We appreciate obtaining access to imaging and phenotypic data on SFARI Base. Approved researchers can obtain the Simons VIP population dataset described in this study by applying at https://base.sfari.org. We are grateful to all families who participated in the 16p11.2 European Consortium. Dr. P. Thompson was funded in part by the U.S. NIH grants R01MH116147, P41EB015922, R01MH111671, and U01 AG068057. Ms. Petra Tamer received the Canadian Institute of Health Research (CIHR) Scholarship.
BACKGROUND: Polygenicity and genetic heterogeneity pose great challenges for studying psychiatric conditions. Genetically informed approaches have been implemented in neuroimaging studies to address this issue. However, the effects on functional connectivity of rare and common genetic risks for psychiatric disorders are largely unknown. Our objectives were to estimate and compare the effect sizes on brain connectivity of psychiatric genomic risk factors with various levels of complexity: oligogenic copy number variants (CNVs), multigenic CNVs, and polygenic risk scores (PRSs) as well as idiopathic psychiatric conditions and traits.METHODS: Resting-state functional magnetic resonance imaging data were processed using the same pipeline across 9 datasets. Twenty-nine connectome-wide association studies were performed to characterize the effects of 15 CNVs (1003 carriers), 7 PRSs, 4 idiopathic psychiatric conditions (1022 individuals with autism, schizophrenia, bipolar conditions, or attention-deficit/hyperactivity disorder), and 2 traits (31,424 unaffected control subjects).RESULTS: Effect sizes on connectivity were largest for psychiatric CNVs (estimates: 0.2-0.65 z score), followed by psychiatric conditions (0.15-0.42), neuroticism and fluid intelligence (0.02-0.03), and PRSs (0.01-0.02). Effect sizes of CNVs on connectivity were correlated to their effects on cognition and risk for disease (r = 0.9, p = 5.93 × 10-6). However, effect sizes of CNVs adjusted for the number of genes significantly decreased from small oligogenic to large multigenic CNVs (r = -0.88, p = 8.78 × 10-6). PRSs had disproportionately low effect sizes on connectivity compared with CNVs conferring similar risk for disease.CONCLUSIONS: Heterogeneity and polygenicity affect our ability to detect brain connectivity alterations underlying psychiatric manifestations.