In a recent study published in Genome Medicine, researchers characterized the genetic architecture of irritable bowel syndrome (IBS), investigated its genetic overlap with gastrointestinal and psychiatric phenotypes, and identified novel genomic risk loci.
IBS causes recurring stomach discomfort and changes in bowel habits. Gut-brain axis dysregulation, gut motility dysfunction, dysbiosis, and alterations in gut permeability are all factors. A genome-wide association analysis discovered genetic variations, but heritability remains unknown, and overlap with psychiatric diseases remains unquantified beyond genome-level genetic connections.
About the study
In the present study, researchers used data on psychiatric and gastrointestinal disorders to identify novel genetic loci for irritable bowel syndrome (IBS) and, thus, improve our understanding of the underlying biological mechanisms that can be targeted for developing new interventions.
Bivariate casual mixture modeling was performed to assess the polygenic framework of irritable bowel syndrome and quantitatively explore the genomic overlap between the gastrointestinal and psychiatric phenotypes using genome-wide association studies (GWAS) summary statistics of irritable bowel syndrome (53,400 and 433,201 cases and control individuals, respectively).
The identified genetic overlap was leveraged to enhance the identification of IBS-associated genetic loci and identify specific shared loci related to IBS and the gastrointestinal and psychiatric phenotypes using conditional/conjunctional false discovery rates (condFDR/conjFDR). Functional analyses were performed using functional mapping and gene annotation (FUMA).
GWAS summary statistical data for irritable bowel syndrome (IBS) were retrieved from European individuals who participated in the Belly Genes Initiative (BGI) and the United Kingdom Biobank (UKBB) study.
UKBB participants satisfied IBD’s Rome III diagnostic criteria for IBS diagnosis using Digestive Health Questionnaires (DHQs, (24,845 individuals) or received an IBS diagnosis based on the international classification of diseases, tenth revision (ICD-10) codes. BGI participants were diagnosed with inflammatory bowel disease (IBD) based on their electronic health records, questionnaires, and diagnosis by specialists at tertiary care clinics.
Individuals with a history of chronic intestinal disorders such as Crohn’s disease and coeliac disease were excluded from the analysis. GWAS summary statistical data for individuals with generalized anxiety disorder (GAD) were retrieved from Million Veteran Program members, comprising 175,163 European individuals.
GWAS summary statistical data for major depression (MD) were retrieved from a three GWAS-based meta-analytical study of 43,204 European depressed individuals, diagnosed using the psychiatric Genomics Consortium (PGC) criteria, 75,607 cases of self-documented depression, and UKBB participants (233,763 and 127,552 controls and cases, respectively).
GWAS data for bipolar disorder (BIP) were retrieved from the PGC (third wave), including 371,549 and 41,917 controls and cases, respectively, diagnosed using the ICD-9, 10, and the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria.
GWAS statistics were also obtained for schizophrenia (SCZ, from the PGC, 77,258 and 53,386 controls and cases, respectively), diverticular disease [from the UKBB (27,444 cases) and the national biobank of Finland (17,851 patients)], and inflammatory bowel disease (from a 25,052-case meta-analysis).
IBS was highly polygenic, with 12k trait-influencing variants. Extensive polygenic overlap was observed between irritable bowel syndrome and, psychiatric diseases and to a lesser extent, with gastrointestinal disorders. In total, 132 independent IBS-related genetic loci were identified by conditioning on psychiatric diseases (n=127) and gastrointestinal disorders (n=24).
The conjFDR framework showed that 70 unique loci were shared between irritable bowel syndrome and psychiatric diseases. Functional analyses of shared loci showed enrichment for biological mechanisms of the immunological and nervous systems. Genomic associations and shared genetic loci between irritable bowel syndrome subtypes and psychiatric diseases were different.
IBS showed a significant polygenic overlap with psychiatric disorders, with low genetic correlations with bipolar disorder (0.1) and schizophrenia (0.2). The genomic association analyses revealed that 98% and 93% of trait-influencing variants for bipolar disorder and schizophrenia overlap with irritable bowel syndrome, respectively.
However, the majority of the genomic risk loci for IBS are intergenic or intronic, making it difficult to identify trait-influencing variants for highly polygenic, complex phenotypes. The genetic overlap enabled the identification of 132 genomic risk loci for IBS, with 116 being novel.
A total of 70 unique loci were shared between IBS and MD, BIP, SCZ, and GAD, and three loci with diverticular disease, with the majority having a concordant direction of effect.
The two exonic genetic loci identified for irritable bowel syndrome could improve understanding of the shared molecular pathways between irritable bowel syndrome and psychiatric diseases. The single-nucleotide polymorphism (SNP) rs20551, a missense mutation in the EP300 gene, regulates biological pathways of neural plasticity, epithelial cell differentiation, and antimicrobial peptide production in the intestines.
The LRP8 mutation encodes the apolipoprotein R receptor (ApoER2) for Apo-E and Reelin ligands. The Reelin-ApoER2 system impacts neurodevelopmental pathways within the nervous systems of the peripheral and central type and may contribute to the maintenance of the gut barrier functions.
Overall, the study findings showed that the known clinical comorbidity between IBS and gastrointestinal and psychiatric disorders is in part associated with a shared genomic architecture.
Hence, the genomic overlap can be explored to identify novel IBS-related genetic loci and reveal biological mechanisms involved in IBS pathophysiology. Genomic differences may underlie the clinical IBS subtype. The study findings could guide the development of personalized interventions.