The overlapping genetic architecture of psychiatric disorders and cortical brain structure

Abstract

Both psychiatric vulnerability and cortical structure are shaped by the cumulative effect of common genetic variants across the genome. However, the shared genetic underpinnings between psychiatric disorders and brain structural phenotypes, such as thickness and surface area of the cerebral cortex, remain elusive. Here we use pleiotropy-informed conjunctional false discovery rate analysis to investigate shared loci across genome-wide association scans of regional cortical thickness, surface area and eight psychiatric disorders in individuals of European ancestry. Aggregating regional measures, we identified 55 independent genetic loci shared between psychiatric disorders and surface area, as well as 29 independent genetic loci shared with cortical thickness. Risk alleles exhibited bidirectional effects on both cortical thickness and surface area, such that some risk alleles for each disorder were associated with increased regional brain size while other risk alleles were associated with decreased regional brain size. Due to bidirectional effects, in many cases we observed extensive pleiotropy between an imaging phenotype and a psychiatric disorder even in the absence of a significant genetic correlation between them. The impact of genetic risk for psychiatric disorders on regional brain structure did exhibit a consistent pattern across highly comorbid psychiatric disorders, with 80% of the independent genetic loci shared across multiple disorders displaying consistent directions of effect. Cortical patterning of genetic overlap revealed a hierarchical genetic architecture, with the association cortex and sensorimotor cortex representing two extremes of shared genetic influence on psychiatric disorders and brain structural variation. Integrating multiscale functional annotations and transcriptomic profiles, we observed that shared genetic loci were enriched in active genomic regions, converged on neurobiological and metabolic pathways and showed differential expression in postmortem brain tissue from individuals with psychiatric disorders. Cumulatively, these findings provide a significant advance in our understanding of the overlapping polygenic architecture between psychopathology and cortical brain structure. This study highlights sex differences in major depressive disorder using resting-state functional magnetic resonance imaging. Findings suggest hormonal fluctuations influence onset, emphasizing the need for larger investigations to identify sex-specific biomarkers and improve personalized treatment strategies.