Shared genetic architecture between irritable bowel syndrome and psychiatric disorders reveals molecular pathways of the gut-brain axis

Abstract

Background: Irritable bowel syndrome (IBS) often co-occurs with psychiatric and gastrointestinal disorders. A recent genome-wide association study (GWAS) identified several genetic risk variants for IBS. However, most of the heritability remains unidentified, and the genetic overlap with psychiatric and somatic disorders is not quantified beyond genome-wide genetic correlations. Here, we characterize the genetic architecture of IBS, further, investigate its genetic overlap with psychiatric and gastrointestinal phenotypes, and identify novel genomic risk loci.

Methods: Using GWAS summary statistics of IBS (53,400 cases and 433,201 controls), and psychiatric and gastrointestinal phenotypes, we performed bivariate casual mixture model analysis to characterize the genetic architecture and genetic overlap between these phenotypes. We leveraged identified genetic overlap to boost the discovery of genomic loci associated with IBS, and to identify specific shared loci associated with both IBS and psychiatric and gastrointestinal phenotypes, using the conditional/conjunctional false discovery rate (condFDR/conjFDR) framework. We used functional mapping and gene annotation (FUMA) for functional analyses.

Results: IBS was highly polygenic with 12k trait-influencing variants. We found extensive polygenic overlap between IBS and psychiatric disorders and to a lesser extent with gastrointestinal diseases. We identified 132 independent IBS-associated loci (condFDR < 0.05) by conditioning on psychiatric disorders (n = 127) and gastrointestinal diseases (n = 24). Using conjFDR, 70 unique loci were shared between IBS and psychiatric disorders. Functional analyses of shared loci revealed enrichment for biological pathways of the nervous and immune systems. Genetic correlations and shared loci between psychiatric disorders and IBS subtypes were different.

Conclusions: We found extensive polygenic overlap of IBS and psychiatric and gastrointestinal phenotypes beyond what was revealed with genetic correlations. Leveraging the overlap, we discovered genetic loci associated with IBS which implicate a wide range of biological pathways beyond the gut-brain axis. Genetic differences may underlie the clinical subtype of IBS. These results increase our understanding of the pathophysiology of IBS which may form the basis for the development of individualized interventions.

Keywords: Genetic overlap; Gut-brain axis; Irritable bowel syndrome; Psychiatric disorder.

Fig. 1

Conditional Q-Q plots of nominal –log10 p-values vs empirical –log10 p-values in irritable bowel syndrome (IBS) below the standard genome-wide association study threshold of p < 5.0 × 10⁻⁸ as a function of significance of association with generalized anxiety disorder (GAD), major depression (MD), bipolar disorder (BIP), schizophrenia (SCZ), diverticular disease (DVD), or inflammatory bowel disease (IBD) below the level of –log10 p-values of 1, 2, or 3, corresponding to p < 0.10, p < 0.01 and p < 0.001, respectively. The blue line includes all SNPs and dashed lines indicate the null hypothesis

Fig. 2

Polygenicity of irritable bowel syndrome (IBS), generalized anxiety disorder (GAD), major depression (MD) bipolar disorder (BIP), schizophrenia (SCZ), diverticular disease (DVD), inflammatory bowel disease (IBD), and height (HGT) with the number of trait-influencing (“causal”) variants explaining 90% of the heritability (estimated from univariate MiXeR analysis)

Fig. 3

Genome-wide genetic overlap and genetic correlation among irritable bowel syndrome (IBS), generalized anxiety disorder (GAD), major depression (MD) bipolar disorder (BIP), schizophrenia (SCZ), diverticular disease (DVD), inflammatory bowel disease (IBD), and Height (HGT). The numbers in colored Venn diagrams indicate the number of shared and phenotype-specific trait-influencing variants which account for 90% of heritability in thousands, and r_g represents genome-wide genetic correlation. N.B. For GAD, MD, and DVD, the value of minimum AIC was negative — an indicator that the shared component may be smaller than shown in the figure model fit (MiXeR analysis)

Fig. 4

Genetic correlations from LD score regression analyses for subtypes of irritable bowel syndrome (IBS): IBS with constipation (IBSC), IBS with diarrhea (IBSD) and IBS with mixed constipation and diarrhea (IBSM), and psychiatric and gastrointestinal diseases. Generalized anxiety disorder (GAD), major depression (MD), bipolar disorder (BIP), schizophrenia (SCZ), diverticular disease (DVD), or inflammatory bowel disease (IBD)

Fig. 5

A–F Conjunctional FDR Manhattan plot of –log10 (conjFDR) values for loci shared between irritable bowel syndrome (IBS) and other phenotypes: generalized anxiety disorder (GAD), major depression (MD), bipolar disorder (BIP), schizophrenia (SCZ), diverticular disease (DVD) and inflammatory bowel disease (IBD) SNPs with conjunctional –log10(conjFDR) > 1.3 (i.e., conjFDR < 0.05) are shown with large points

Fig. 6

Conjunctional FDR Manhattan plot of –log10 (conjFDR) values for loci shared between different subtypes of irritable bowel syndrome (IBS), and psychiatric disorders and gastrointestinal diseases. Top — IBS with constipation (IBSC), middle — IBS with diarrhea (IBSD), and bottom — IBS with mixed constipation and diarrhea (IBSM). Generalized anxiety disorder (GAD), major depression (MD), bipolar disorder (BIP), schizophrenia (SCZ), diverticular disease (DVD), or inflammatory bowel disease (IBD)