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

Markos Tesfaye; Piotr Jaholkowski; Guy F L Hindley; Alexey A Shadrin; Zillur Rahman; Shahram Bahrami; Aihua Lin; Børge Holen; Nadine Parker; Weiqiu Cheng; Linn Rødevand; Oleksandr Frei; Srdjan Djurovic; Anders M Dale; Olav B Smeland; Kevin S O'Connell; Ole A Andreassen

doi:10.1186/s13073-023-01212-4

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

Genome Med. 2023 Aug 1;15(1):60. doi: 10.1186/s13073-023-01212-4.

Authors

Markos Tesfaye^{1

2}, Piotr Jaholkowski³, Guy F L Hindley^{3

4}, Alexey A Shadrin^{3

5}, Zillur Rahman³, Shahram Bahrami³, Aihua Lin³, Børge Holen³, Nadine Parker³, Weiqiu Cheng³, Linn Rødevand³, Oleksandr Frei^{3

6}, Srdjan Djurovic^{7

8}, Anders M Dale^{9

10

11

12}, Olav B Smeland³, Kevin S O'Connell³, Ole A Andreassen^{13

14}

Affiliations

¹ NORMENT, Centre for Mental Disorders Research, Division of Mental Health and Addiction, Oslo University Hospital, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. m.t.woldeyohannes@medisin.uio.no.
² NORMENT, Department of Clinical Sciences, University of Bergen, Bergen, Norway. m.t.woldeyohannes@medisin.uio.no.
³ NORMENT, Centre for Mental Disorders Research, Division of Mental Health and Addiction, Oslo University Hospital, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁴ Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
⁵ KG Jebsen Centre for Neurodevelopmental Disorders, University of Oslo and Oslo University Hospital, Oslo, Norway.
⁶ Center for Bioinformatics, Department of Informatics, University of Oslo, Oslo, Norway.
⁷ NORMENT, Department of Clinical Sciences, University of Bergen, Bergen, Norway.
⁸ Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
⁹ Department of Radiology, University of California, San Diego, La Jolla, CA, USA.
¹⁰ Multimodal Imaging Laboratory, University of California San Diego, La Jolla, CA, USA.
¹¹ Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA.
¹² Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
¹³ NORMENT, Centre for Mental Disorders Research, Division of Mental Health and Addiction, Oslo University Hospital, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. o.a.andreassen@medisin.uio.no.
¹⁴ KG Jebsen Centre for Neurodevelopmental Disorders, University of Oslo and Oslo University Hospital, Oslo, Norway. o.a.andreassen@medisin.uio.no.

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.

Publication types

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

MeSH terms

Brain-Gut Axis
Gastrointestinal Diseases*
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Irritable Bowel Syndrome* / complications
Irritable Bowel Syndrome* / genetics
Mental Disorders* / genetics
Polymorphism, Single Nucleotide