Genetic Heterogeneity Shapes Brain Connectivity in Psychiatry

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. LindenAurelie Labbe, Sarah Lippé, Carrie E. Bearden, Laura Almasy, David C. Glahn, Paul M. Thompson, Thomas Bourgeron, Pierre Bellec, Sebastien Jacquemont

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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: 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.

Original languageEnglish
Pages (from-to)45-58
Number of pages14
JournalBiological Psychiatry
Volume93
Issue number1
DOIs
StatePublished - 1 Jan 2023
Externally publishedYes

Keywords

  • Autism spectrum disorder
  • Copy number variant
  • Functional connectivity
  • Genetic heterogeneity
  • Polygenic score
  • Transdiagnostic approach

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