RESUMEN
Somatoform traits, which manifest as persistent physical symptoms without a clear medical cause, are prevalent and pose challenges to clinical practice. Understanding the genetic basis of these disorders could improve diagnostic and therapeutic approaches. With publicly available summary statistics, we conducted a multivariate genome-wide association study (GWAS) and multi-omic analysis of four somatoform traits-fatigue, irritable bowel syndrome, pain intensity, and health satisfaction-in 799,429 individuals genetically similar to Europeans. 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. These biological insights provide promising avenues for treatment development.
RESUMEN
Tobacco use disorder (TUD) is the most prevalent substance use disorder in the world. Genetic factors influence smoking behaviours and although strides have been made using genome-wide association studies to identify risk variants, most variants identified have been for nicotine consumption, rather than TUD. Here we leveraged four US biobanks to perform a multi-ancestral meta-analysis of TUD (derived via electronic health records) in 653,790 individuals (495,005 European, 114,420 African American and 44,365 Latin American) and data from UK Biobank (ncombined = 898,680). We identified 88 independent risk loci; integration with functional genomic tools uncovered 461 potential risk genes, primarily expressed in the brain. TUD was genetically correlated with smoking and psychiatric traits from traditionally ascertained cohorts, externalizing behaviours in children and hundreds of medical outcomes, including HIV infection, heart disease and pain. This work furthers our biological understanding of TUD and establishes electronic health records as a source of phenotypic information for studying the genetics of TUD.
Asunto(s)
Tabaquismo , Humanos , Tabaquismo/genética , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Estados Unidos/epidemiología , Masculino , Femenino , Registros Electrónicos de SaludRESUMEN
Tobacco use disorder (TUD) is the most prevalent substance use disorder in the world. Genetic factors influence smoking behaviors, and although strides have been made using genome-wide association studies (GWAS) to identify risk variants, the majority of variants identified have been for nicotine consumption, rather than TUD. We leveraged five biobanks to perform a multi-ancestral meta-analysis of TUD (derived via electronic health records, EHR) in 898,680 individuals (739,895 European, 114,420 African American, 44,365 Latin American). We identified 88 independent risk loci; integration with functional genomic tools uncovered 461 potential risk genes, primarily expressed in the brain. TUD was genetically correlated with smoking and psychiatric traits from traditionally ascertained cohorts, externalizing behaviors in children, and hundreds of medical outcomes, including HIV infection, heart disease, and pain. This work furthers our biological understanding of TUD and establishes EHR as a source of phenotypic information for studying the genetics of TUD.