Genetic heterogeneity shapes brain connectivity in psychiatry
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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