1. Brain functional connectivity mirrors genetic pleiotropy in psychiatric conditions
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Clara A Moreau, Kuldeep Kumar, Annabelle Harvey, Guillaume Huguet, Sebastian G W Urchs, Laura M Schultz, Hanad Sharmarke, Khadije Jizi, Charles-Olivier Martin, Nadine Younis, Petra Tamer, Jean-Louis Martineau, Pierre Orban, Ana Isabel Silva, Jeremy Hall, Marianne B M van den Bree, Michael J Owen, David E J Linden, Sarah Lippé, Carrie E Bearden, Laura Almasy, David C Glahn, Paul M Thompson, Thomas Bourgeron, Pierre Bellec, Sebastien Jacquemont, 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 Montreal (CRIUGM), Université de Montréal (UdeM), McGill University = Université McGill [Montréal, Canada], Children’s Hospital of Philadelphia (CHOP ), Centre de Recherche de l'Institut Universitaire de Gériatrie de Montréal (CRIUGM), Centre de Recherche de l’Institut Universitaire en Santé Mentale de Montréal (CRIUSMM), Cardiff University, Maastricht University [Maastricht], University of California [Los Angeles] (UCLA), University of California (UC), Semel Institute for Neuroscience and Human Behavior [Los Angeles, Ca], University of California (UC)-University of California (UC), University of Pennsylvania, Keck School of Medicine [Los Angeles], University of Southern California (USC), 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, IVADO, Canada First Research Excellence Fund (Healthy Brain Healthy Lives) (S.J.). S.J. 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 ‘Fondation Brain Canada’ Multi-Investigator initiative (S.J.) and a grant from The Canadian Institutes of Health Research (CIHR 400528, S.J.). 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). The CHUV cohort was supported by the Swiss National Science Foundation (Maillard Anne, Project, PMPDP3 171331). Data from the UCLA cohort provided by C.E.B. (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 National Institutes of Health Roadmap for Medical Research grants UL1-DE019580, RL1MH083268, RL1MH083269, RL1DA024853, RL1MH083270, RL1LM009833, PL1MH083271 and PL1NS062410. P.B. 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 (P.B.). This work was supported by Simons Foundation grant nos. SFARI219193 and SFARI274424. We thank all of the families at the participating SVIP (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. P.M.T. was funded in part by the National Institutes of Health grants R01MH116147, P41EB015922, R01MH111671 and U01 AG068057. P.T. received the Canadian Institute of Health Research (CIHR) Scholarship., RS: MHeNs - R2 - Mental Health, Psychiatry 1, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, School for Mental Health & Neuroscience, and RS: MHeNs - R3 - Neuroscience
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copy-number variant ,pleiotropy ,functional connectivity ,autism spectrum disorder ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Neurology (clinical) ,psychiatry - Abstract
Pleiotropy occurs when a genetic variant influences more than one trait. This is a key property of the genomic architecture of psychiatric disorders and has been observed for rare and common genomic variants. It is reasonable to hypothesize that the microscale genetic overlap (pleiotropy) across psychiatric conditions and cognitive traits may lead to similar overlaps at the macroscale brain level such as large-scale brain functional networks. We took advantage of brain connectivity, measured by resting-state functional MRI to measure the effects of pleiotropy on large-scale brain networks, a putative step from genes to behaviour. We processed nine resting-state functional MRI datasets including 32 726 individuals and computed connectome-wide profiles of seven neuropsychiatric copy-number-variants, five polygenic scores, neuroticism and fluid intelligence as well as four idiopathic psychiatric conditions. Nine out of 19 pairs of conditions and traits showed significant functional connectivity correlations (rFunctional connectivity), which could be explained by previously published levels of genomic (rGenetic) and transcriptomic (rTranscriptomic) correlations with moderate to high concordance: rGenetic—rFunctional connectivity = 0.71 [0.40–0.87] and rTranscriptomic—rFunctional connectivity = 0.83 [0.52; 0.94]. Extending this analysis to functional connectivity profiles associated with rare and common genetic risk showed that 30 out of 136 pairs of connectivity profiles were correlated above chance. These similarities between genetic risks and psychiatric disorders at the connectivity level were mainly driven by the overconnectivity of the thalamus and the somatomotor networks. Our findings suggest a substantial genetic component for shared connectivity profiles across conditions and traits, opening avenues to delineate general mechanisms—amenable to intervention—across psychiatric conditions and genetic risks.
- Published
- 2023
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