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

Abstract

Background 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. Methods 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. Key Results 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% (hSNP2 = 0.047, p = 0.014). Genetic correlations indicate FD predisposition is shared with several other diseases and traits (rg > 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. Conclusions & Inferences 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.

British Society of Gastroenterology guidelines on the management of functional dyspepsia

“… 51 106 A more recent large-scale survey of comorbidity and genetic predisposition in FD confirmed a weak heritability of only 5%, but also suggested considerable clinical and genetic overlap with other conditions, including other gastrointestinal disorders, such as IBS and gastro-oesophageal reflux disease (GORD), personality traits, mood disorders and, interestingly, non-gastrointestinal diseases, such as rheumatological disorders and, to a lesser extent, cardiovascular disease. 106 This study also suggested genes likely to play a role in FD, namely those involved in synaptic transmission and neuroplasticity, and gastrointestinal development and integrity. However, additional large-scale studies are required to confirm these findings and identify other potential gene candidates.…”

The role of M1 to M2 macrophage polarization in the etiology of idiopathic gastroparesis: GWAS perspective

“…This reinforces the capacity to subgroup cases based on diabetes risk score. This is presented in the Supplementary Material Figure 2 Additionally, we explored the frequencies of previously reported variants in a functional dyspepsia GWAS 11 . Two variants previously reported came out as nominally significant: rs2595968 (NFASC p -value<0.004) and rs17597505 ( p -value<0.03).…”

Multi-omics analysis reveals the metabolic regulators of duodenal low-grade inflammation in a functional dyspepsia model

“…A recent study with a large sample size reported FD and other gastrointestinal disorders shares several commonalities in a wide spectrum of pathophysiology, which increases the difficulty of treatment against a specific disease ( 15 ). Compared to a global exploration, it is more important to profile the comprehensive features locally.…”