T23. MULTIVARIATE, MULTIOMIC ANALYSIS IN 799,429 INDIVIDUALS IDENTIFIES 134 LOCI ASSOCIATED WITH SOMATOFORM TRAITS

Somatoform traits, which manifest as persistent physical symptoms without a clear medical cause, are prevalent and pose significant challenges to clinical practice. Persistent physical symptoms have complex etiologies and often co-occur with one another and with psychiatric disorders. Their co-occurrence with psychiatric disorders has led to their inclusion in empirically based models of psychopathology, including the Hierarchical Taxonomy of Psychopathology (HiTOP). Understanding the genetic basis of these traits could improve diagnostic and therapeutic approaches and inform psychiatric nosology models. With publicly available summary statistics, we conducted a multivariate genome-wide association study (GWAS) and multiomic analysis of four somatoform traits—fatigue, irritable bowel syndrome, pain intensity, and health satisfaction—in an effective sample size of 799,429 individuals genetically similar to European reference panels. Additionally, we conducted drug repurposing analyses to identify potential druggable targets and Mendelian randomization analyses to identify potential causal effects of gut microbiota abundance on somatoform traits. Using genomic structural equation modeling, GWAS identified 134 loci significantly associated with a somatoform common factor, including 44 loci not significant in the input GWAS and 8 novel loci for somatoform traits. Gene-property analyses highlighted an enrichment of genes involved in synaptic transmission and enriched gene expression in 12 brain tissues. Six genes, including members of the CD300 family, had putatively causal effects mediated by protein abundance. There was substantial polygenic overlap (76-83%) between the somatoform and externalizing, internalizing, and general psychopathology factors. Somatoform polygenic scores were associated most strongly with obesity, Type 2 diabetes, tobacco use disorder, and mood/anxiety disorders in independent biobanks. Drug repurposing analyses suggested potential therapeutic targets, including MEK inhibitors. Mendelian randomization indicated potentially protective effects of gut microbiota, including Ruminococcus bromii. Consistent with emerging medical and genetic knowledge, somatoform traits have a shared etiology and considerable polygenic overlap with psychopathology. Given the high polygenic and phenotypic overlap with psychopathology, our results support the inclusion of a proposed somatoform spectrum in the HiTOP framework. These findings underscore the need for treatment approaches that recognize the interconnectedness of physical and mental health. The biological insights from drug repurposing and Mendelian randomization analyses could provide promising avenues for treatment development.