A survey of functional dyspepsia in 361,360 individuals: Phenotypic and genetic cross-disease analyses

Functional dyspepsia (FD) is a common gastrointestinal condition of poorly understood pathophysiology. While symptoms' overlap with other conditions may indicate common pathogenetic mechanisms, genetic predisposition is suspected but has not been adequately investigated.

Using healthcare, questionnaire, and genetic data from three large population-based biobanks (UK Biobank, EGCUT, and MGI), we surveyed FD comorbidities, heritability, and genetic correlations across a wide spectrum of conditions and traits in 10,078 cases and 351,282 non-FD controls of European ancestry.

In UK Biobank, 281 diagnoses were detected at increased prevalence in FD, based on healthcare records. Among these, gastrointestinal conditions (OR = 4.0, p < 1.0 × 10^-300 ), anxiety disorders (OR = 2.3, p < 1.4 × 10^-27 ), ischemic heart disease (OR = 2.2, p < 2.3 × 10^-76 ), and infectious and parasitic diseases (OR = 2.1, p = 1.5 × 10^-73 ) showed strongest association with FD. Similar results were obtained in an analysis of self-reported conditions and use of medications from questionnaire data. Based on a genome-wide association meta-analysis of genotypes across all cohorts, FD heritability was estimated close to 5% ( $h_{\text{SNP}}^2$  = 0.047, p = 0.014). Genetic correlations indicate FD predisposition is shared with several other diseases and traits (r_g  > 0.344), mostly overlapping with those also enriched in FD patients. Suggestive (p < 5.0 × 10^-6 ) association with FD risk was detected for 13 loci, with 2 showing nominal replication (p < 0.05) in an independent cohort of 192 FD patients.

FD has a weak heritable component that shows commonalities with multiple conditions across a wide spectrum of pathophysiological domains. This new knowledge contributes to a better understanding of FD etiology and may have implications for improving its treatment.