A Genome-Wide Meta-Analysis of Functional Dyspepsia in 1,168,899 Individuals Implicates Immune Pathways in Disease...

Functional dyspepsia (FD) affects over 7% of the global population, impairing quality of life and driving significant healthcare burden. Although genetic contributions to FD pathophysiology have been suspected, large, well-powered genetic studies remain limited. We aimed to identify FD genetic risk factors and implicated biological pathways.

We performed a FD genome-wide association study in 1,168,899 European individuals, including 29,584 FD cases from five large biobanks. We dissected the genetic architecture of FD and its overlap with gastrointestinal and psychiatric disorders and conducted comprehensive gene-prioritization, regulatory, and cell-type enrichment analyzes to identify pathophysiological mechanisms and actionable targets.

We show FD is a complex, highly polygenic trait with a significant genetic component (3.63% heritability) but lower than similar gastrointestinal disorders like irritable bowel syndrome (IBS) and gastroesophageal reflux disease (GERD). Mendelian randomization revealed causal effects of depression and anxiety on FD risk. We observed substantial local genetic correlations with IBS and GERD, including shared genome-wide significant signals at the human leukocyte antigen region, supporting immune-mediated mechanisms. Gene-prioritization analyzes converged on DEAH-Box Helicase 36 (DHX36), involved in immune responses to microbial infections. Integrative expression-quantitative trait loci and colocalization analyzes indicated that higher genetic risk of FD is causally associated with a reduced DHX36 expression in gastrointestinal tissues, potentially triggering increased proinflammatory cytokine production.

This study implicates immune-driven pathways in FD susceptibility, adds insights into the pathophysiological mechanisms of the disease, and reveals DHX36 as a candidate target for future investigation.