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

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.

A Unifying Statistical Framework to Discover Disease Genes from GWAS

“…All probabilities were computed with the biochemical prior. Traits: BMI, body mass index (Neale et al, 2021); SCZ, schizophrenia (Psychiatric Genomics Consortium, 2021); IBD, inflammatory bowel disease (de Lange et al, 2017); BPD, bipolar disorder (Mullins et al, 2021); DEP, depression (Howard et al, 2019); PD, Parkinson’s disease (Nalls et al, 2019); MIG, migraine (Canela-Xandri et al, 2018); IBS, irritable bowel syndrome (Eijsbouts et al, 2021). For each trait, the leftmost bar indicates the expected value of the number of causal variants (i.e., the total number of independent detectable signals in the GWAS), considering only putative causal variants with a GWAS p-value smaller than 10 −3 .…”

Irritable bowel syndrome and microbiome; Switching from conventional diagnosis and therapies to personalized interventions

“…A recently published genome-wide association study including 53,400 people with IBS and 433,201 controls, identified six independent genetic susceptibility loci for IBS at genome-wide significance (P < 5 × 10 − 8) and all six loci were replicated at Bonferroni significance (P < 0.0083) using data from an independent panel from 23andMe (205,252 cases and 1,384,055 controls). This study reported strong genome-wide association between IBS and mood and anxiety disorders rooted to shared pathogenic pathways [ 30 ]. Due to the important role of serotonin in the brain–gut axis, genetics of serotonergic pathways, especially the serotonin transporter (SERT), have gained a great amount of attention in recent years [ 31 ].…”

“…External factors are dominant, but internal factors such as gut microbiome, gastrointestinal immune system and genetic makeup is also likely to be crucial for the development and progression of symptoms. Here we summarized potential external and internal factors and genetic findings linked to underlying pathophysiological mechanisms of IBS [ 6 , 24 , 26 , 30 , 96 ]. HPA, hypothalamic–pituitary–adrenal axis; ADRA, adrenoceptor-α; aINS, anterior insula; CDC42, cell division cycle 42; CDH1, cadherin 1; CGN, cingulin; CLDN, claudin; COMT, catechol-O-methyltransferase; CRHR1, corticotropin-releasing hormone receptor 1; FGFR4, fibroblast growth factor receptor 4; GLUL, glutamate-ammonia ligase; GPBAR1, G protein-coupled bile acid receptor 1; GRID2IP, GRID2-interacting protein; HTR, 5-hydroxytryptamine receptor; IL, interleukin; KLB, Klotho-β; mir, microRNA; NKRF, nuclear factor-κB-repressing factor; SCN5A, sodium voltage-gated channel α-subunit 5; SLC6A4, solute carrier family 6 member 4; TNF, tumour necrosis factor; TNFSF15, TNF superfamily member 15; TRPV1, transient receptor potential cation channel subfamily V member 1;; NCAM1, Neural Cell Adhesion Molecule 1; CADM2, Cell Adhesion Molecule 2; PHF2, PHD Finger Protein 2; DOCK9, Dedicator Of Cytokinesis 9 …”

Fixing Functional GI Disorders Using Microbes: Easier Said Than Done

“…Genetic elements are believed to be playing a role in the enteric nervous system ( 21 ), and one study using patient questionnaires that included participants not diagnosed with IBS, proposed a link between six genetic susceptibility loci and IBS ( 22 ). Nevertheless, despite the promise of human genetics the causes of FGID do not appear to be primarily genetically linked.…”