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Genetic heterogeneity shapes brain connectivity in psychiatry

Clara Moreau 1, 2, 3 Annabelle Harvey 2, 3 Kuldeep Kumar 2 Guillaume Huguet 2 Sebastian Urchs 3, 4 Elise Douard 2 Laura Schultz 5 Hanad Sharmarke 3 Khadije Jizi 2 Charles-Olivier Martin 2 Nadine Younis 2 Petra Tamer 2 Thomas Rolland 1 Jean-Louis Martineau Pierre Orban 6, 7 Ana Isabel Silva Jeremy Hall 8 Marianne B.M. van den Bree 8 Michael Owen 8 David E.J. Linden 8, 9 Aurelie Labbe 10 Sarah Lippé Carrie Bearden 11 Laura Almasy 12 David Glahn 13, 14 Paul Thompson Thomas Bourgeron 1 Pierre Bellec 15 Sebastien Jacquemont 2 
Abstract : 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: oligo-, multi-genic copy number variants (CNVs), and polygenic risk scores (PRS) as well as idiopathic psychiatric conditions and traits. Methods Resting-state functional-MRI data were processed using the same pipeline across nine datasets. Twenty-nine connectome-wide association studies were performed to characterize the effects of 15 CNVs (1003 carriers), 7 PRS, 4 idiopathic psychiatric conditions (1022 individuals with either autism, schizophrenia, bipolar conditions, or ADHD), and 2 traits (31424 unaffected controls). Results Effect sizes on connectivity were largest for psychiatric CNVs (estimates: 0.2 to 0.65 z-score) followed by psychiatric conditions (0.15 to 0.42), neuroticism and fluid intelligence (0.02 to 0.03), and PRS (0.01 to 0.02). Effect-sizes of CNVs on connectivity were correlated to their effects on cognition and risk for disease (r=0.9, p=5.93e-06). However, effect sizes of CNVs adjusted for the number of genes significantly decreased from small oligogenic to large multigenic CNVs (r=-0.88, p=8.78e-06). PRS had disproportionately low effect sizes on connectivity compared to CNVs conferring similar risk for disease. Conclusion Heterogeneity and polygenicity impact our ability to detect brain connectivity alterations underlying psychiatric manifestations.
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Submitted on : Thursday, October 20, 2022 - 4:06:47 PM
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Clara Moreau, Annabelle Harvey, Kuldeep Kumar, Guillaume Huguet, Sebastian Urchs, et al.. Genetic heterogeneity shapes brain connectivity in psychiatry. Biological Psychiatry, 2023, 93 (1), pp.54-58. ⟨10.1016/j.biopsych.2022.08.024⟩. ⟨pasteur-03819076⟩



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