Genome-wide multi-trait analysis of irritable bowel syndrome and related mental conditions identifies 38 new genetic hits

Abstract

Background: Irritable bowel syndrome (IBS) is a chronic disorder of gut-brain interaction frequently accompanied by mental conditions, including depression and anxiety. Despite showing substantial heritability and being partly determined by a genetic component, the genetic underpinnings explaining the high rates of comorbidity remain largely unclear and there are no conclusive data on the temporal relationship between them. Exploring the overlapping genetic architecture between IBS and mental conditions may help to identify novel genetic loci and biological mechanisms underlying IBS and causal relationships between them. Methods: We quantified the genetic overlap between IBS, neuroticism, depression and anxiety, conducted a multi-trait genome-wide association study (GWAS) considering these traits and investigated causal relationships between them by using the largest GWAS to date. Results: IBS showed to be a highly polygenic disorder with extensive genetic sharing with mental conditions. Multi-trait analysis of IBS and neuroticism, depression and anxiety identified 42 genome-wide significant hits for IBS, of which 38 are novel. Fine-mapping risk loci highlighted 289 genes upregulated during early embryonic brain development and gene-sets related with psychiatric, digestive and autoimmune disorders. IBS-associated genes were enriched for target genes of anti-inflammatory and antirheumatic drugs, anesthetics and opioid dependence pharmacological treatment. Mendelian-randomization analysis accounting for correlated pleiotropy identified bidirectional causal effects between IBS and neuroticism and depression and causal effects of the genetic liability of IBS on anxiety. Conclusions: These findings provide evidence of the polygenic architecture of IBS, identify novel hits for IBS and extend previous knowledge on the genetic overlap and relationship between gastrointestinal and mental disorders.

Evolutionary medicine approaches to chronic disease: The case of irritable bowel syndrome

“…Another core tenant of evolutionary medicine is gene‐by‐environment interactions, and recent genetic studies have identified potential epigenetic factors explaining the links between the brain–gut axis and IBS. While IBS is polygenic, with numerous genes having mild effects on disease outcome, several genome‐wide association studies have identified certain genetic variants that are connected to both depression and anxiety (via serotonin reuptake) and IBS 14,89 . The epigenetic role of the gut microbiome as a mediator between genes and environment has been proposed as a potential explanation for how these gene‐by‐environment interactions occur in IBS patients and warrants further investigation 15 …”

“…While IBS is polygenic, with numerous genes having mild effects on disease outcome, several genome-wide association studies have identified certain genetic variants that are connected to both depression and anxiety (via serotonin reuptake) and IBS. 14,89 The epigenetic role of the gut microbiome as a mediator between genes and environment has been proposed as a potential explanation for how these gene-by-environment interactions occur in IBS patients and warrants further investigation. 15 The link between mental health and IBS demonstrates that this evolved survival response presents a mismatch with current lifestyles and stress profiles in the industrialized world.…”

Causality of genetically determined blood metabolites on irritable bowel syndrome: A Mendelian randomization study

“…However, the underlying mechanisms of IBS remain poorly understood, encompassing a range of characteristics including gastrointestinal motility, visceral hypersensitivity, intestinal secretion and intestinal permeability [2,4]. It is important to acknowledge that genome-wide association studies (GWAS) have identified numerous genetic variations that enhance the vulnerability of individuals to IBS, thereby offering molecular insights into the complex interplay between environmental and genetic factors in the pathogenesis of IBS [5,6].…”