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

Sílvia Alemany, María Soler Artigas, Judit Cabana-Domínguez, Dana Fakhreddine, Natalia Llonga, L Vilar-Ribó, Amanda Rodríguez-Urrutia, Judit Palacio, Ana Maria González Castro, Beatriz Lobo Álvarez, Carmen Alonso Cotoner, Magnus Simrén, Javier Santos, Josep Antoni Ramos-Quiroga, Marta Ribasés Haro

Research output: Contribution to journalArticleResearchpeer-review

3 Citations (Scopus)

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 variants for IBS, of which 38 are novel. Fine-mapping risk loci highlighted 289 genes enriched in 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 genome-wide significant variants for IBS and extend previous knowledge on the genetic overlap and relationship between gastrointestinal and mental disorders.

Original languageEnglish
Article number272
JournalJournal of Translational Medicine
Volume21
DOIs
Publication statusPublished - 21 Apr 2023

Keywords

  • Anxiety
  • Depression
  • Irritable bowel syndrome (IBS)
  • Multi-trait genome-wide association study (MTAG)
  • Neuroticism

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