Whole exome sequencing analyses reveal gene-microbiota interactions in the context of IBD

Shixian Hu; Arnau Vich Vila; Ranko Gacesa; Valerie Collij; Christine Stevens; Jack M Fu; Isaac Wong; Michael E Talkowski; Manuel A Rivas; Floris Imhann; Laura Bolte; Hendrik van Dullemen; Gerard Dijkstra; Marijn C Visschedijk; Eleonora A Festen; Ramnik J Xavier; Jingyuan Fu; Mark J Daly; Cisca Wijmenga; Alexandra Zhernakova; Alexander Kurilshikov; Rinse K Weersma

doi:10.1136/gutjnl-2019-319706

Whole exome sequencing analyses reveal gene-microbiota interactions in the context of IBD

Gut. 2021 Feb;70(2):285-296. doi: 10.1136/gutjnl-2019-319706. Epub 2020 Jul 10.

Authors

Shixian Hu^{1

2}, Arnau Vich Vila^{1

2}, Ranko Gacesa^{1

2}, Valerie Collij^{1

2}, Christine Stevens³, Jack M Fu^{4

5

6}, Isaac Wong^{4

5}, Michael E Talkowski^{4

5

6

7

8}, Manuel A Rivas⁹, Floris Imhann^{1

2}, Laura Bolte^{1

2}, Hendrik van Dullemen¹, Gerard Dijkstra¹, Marijn C Visschedijk¹, Eleonora A Festen¹, Ramnik J Xavier^{10

11}, Jingyuan Fu^{2

12}, Mark J Daly³, Cisca Wijmenga², Alexandra Zhernakova², Alexander Kurilshikov², Rinse K Weersma¹³

Affiliations

¹ Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
² Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
³ Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
⁴ Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA.
⁵ Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
⁶ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁷ Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts, USA.
⁸ Stanley Center for Psychiatric Research, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
⁹ Department of Biomedical Data Science, Stanford University, Stanford, California, USA.
¹⁰ Center for Microbiome Informatics and Therapeutic, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
¹¹ Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA.
¹² Department of Pediatrics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
¹³ Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands r.k.weersma@mdl.umcg.nl.

Abstract

Objective: Both the gut microbiome and host genetics are known to play significant roles in the pathogenesis of IBD. However, the interaction between these two factors and its implications in the aetiology of IBD remain underexplored. Here, we report on the influence of host genetics on the gut microbiome in IBD.

Design: To evaluate the impact of host genetics on the gut microbiota of patients with IBD, we combined whole exome sequencing of the host genome and whole genome shotgun sequencing of 1464 faecal samples from 525 patients with IBD and 939 population-based controls. We followed a four-step analysis: (1) exome-wide microbial quantitative trait loci (mbQTL) analyses, (2) a targeted approach focusing on IBD-associated genomic regions and protein truncating variants (PTVs, minor allele frequency (MAF) >5%), (3) gene-based burden tests on PTVs with MAF <5% and exome copy number variations (CNVs) with site frequency <1%, (4) joint analysis of both cohorts to identify the interactions between disease and host genetics.

Results: We identified 12 mbQTLs, including variants in the IBD-associated genes IL17REL, MYRF, SEC16A and WDR78. For example, the decrease of the pathway acetyl-coenzyme A biosynthesis, which is involved in short chain fatty acids production, was associated with variants in the gene MYRF (false discovery rate <0.05). Changes in functional pathways involved in the metabolic potential were also observed in participants carrying rare PTVs or CNVs in CYP2D6, GPR151 and CD160 genes. These genes are known for their function in the immune system. Moreover, interaction analyses confirmed previously known IBD disease-specific mbQTLs in TNFSF15.

Conclusion: This study highlights that both common and rare genetic variants affecting the immune system are key factors in shaping the gut microbiota in the context of IBD and pinpoints towards potential mechanisms for disease treatment.

Keywords: genetics; inflammatory bowel disease; intestinal microbiology.

Publication types

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

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Adult
Case-Control Studies
DNA Copy Number Variations / genetics
Exome Sequencing*
Female
Gastrointestinal Microbiome / genetics*
Gene Frequency / genetics
Genetic Predisposition to Disease / genetics*
Humans
Inflammatory Bowel Diseases / etiology*
Inflammatory Bowel Diseases / genetics
Inflammatory Bowel Diseases / microbiology
Male
Membrane Proteins / genetics
Metagenomics
Middle Aged
Quantitative Trait Loci / genetics
Receptors, Interleukin-17 / genetics
Transcription Factors / genetics
Vesicular Transport Proteins / genetics

Substances

Adaptor Proteins, Signal Transducing
CABIN1 protein, human
IL17REL protein, human
Membrane Proteins
Myrf protein, human
Receptors, Interleukin-17
SEC16A protein, human
Transcription Factors
Vesicular Transport Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding