Genome-wide analysis of 53,400 people with irritable bowel syndrome highlights shared genetic pathways with mood and anxiety disorders

Nat Genet. 2021 Nov;53(11):1543-1552. doi: 10.1038/s41588-021-00950-8. Epub 2021 Nov 5.

Abstract

Irritable bowel syndrome (IBS) results from disordered brain-gut interactions. Identifying susceptibility genes could highlight the underlying pathophysiological mechanisms. We designed a digestive health questionnaire for UK Biobank and combined identified cases with IBS with independent cohorts. We conducted a genome-wide association study with 53,400 cases and 433,201 controls and replicated significant associations in a 23andMe panel (205,252 cases and 1,384,055 controls). Our study identified and confirmed six genetic susceptibility loci for IBS. Implicated genes included NCAM1, CADM2, PHF2/FAM120A, DOCK9, CKAP2/TPTE2P3 and BAG6. The first four are associated with mood and anxiety disorders, expressed in the nervous system, or both. Mirroring this, we also found strong genome-wide correlation between the risk of IBS and anxiety, neuroticism and depression (rg > 0.5). Additional analyses suggested this arises due to shared pathogenic pathways rather than, for example, anxiety causing abdominal symptoms. Implicated mechanisms require further exploration to help understand the altered brain-gut interactions underlying IBS.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Anxiety Disorders / genetics*
  • CD56 Antigen / genetics
  • Cell Adhesion Molecules / genetics
  • Cytoskeletal Proteins / genetics
  • Female
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Guanine Nucleotide Exchange Factors / genetics
  • Homeodomain Proteins / genetics
  • Humans
  • Irritable Bowel Syndrome / epidemiology
  • Irritable Bowel Syndrome / genetics*
  • Male
  • Middle Aged
  • Molecular Chaperones / genetics
  • Mood Disorders / genetics*
  • Polymorphism, Single Nucleotide
  • United Kingdom / epidemiology

Substances

  • BAG6 protein, human
  • CADM2 protein, human
  • CD56 Antigen
  • CKAP2 protein, human
  • Cell Adhesion Molecules
  • Cytoskeletal Proteins
  • DOCK9 protein, human
  • Guanine Nucleotide Exchange Factors
  • Homeodomain Proteins
  • Molecular Chaperones
  • NCAM1 protein, human
  • PHF2 protein, human