The shared genetic architecture between schizophrenia and common peripheral organ imaging phenotypes.

Abstract

Schizophrenia (SCZ) is a complex neuropsychiatric disorder that profoundly disrupts daily life. Beyond its well-documented effects on the brain, SCZ is also associated with peripheral organ dysfunction, yet the underlying shared genetic mechanisms remain unclear. In this study, leveraging large-scale genome-wide association study (GWAS) data, we investigated the genetic architecture shared between SCZ and 47 common imaging phenotypes spanning three major peripheral organs: 28 cardiac magnetic resonance (CMR) phenotypes, eight skeletal dual-energy X-ray absorptiometry (DXA) phenotypes, and 11 abdominal magnetic resonance imaging (MRI) phenotypes. We identified seven significant causal associations between SCZ and peripheral organ imaging phenotypes, alongside 99 unique loci through local genetic correlation analysis. Additionally, we pinpointed 437 independent pleiotropic SNPs between SCZ and CMR phenotypes, 257 for skeletal DXA phenotypes, and 230 for abdominal MRI phenotypes. The shared genes were significantly enriched in synapse-related biological processes, underscoring their vital role in SCZ across various peripheral organ systems. Furthermore, we characterized the spatiotemporal expression patterns of shared genes in the brain across different peripheral imaging phenotype groups and identified drug-gene interactions, highlighting potential therapeutic targets for SCZ-related peripheral dysfunction. Our findings underscore the systemic nature of SCZ, emphasizing the need to integrate psychiatric and systemic health perspectives in its management. By revealing novel genetic links and potential therapeutic targets, this study provides valuable insights into SCZ's multifaceted impact beyond the brain.