PT  - JOURNAL ARTICLE
AU  - Shixian Hu
AU  - Arnau Vich Vila
AU  - Ranko Gacesa
AU  - Valerie Collij
AU  - Christine Stevens
AU  - Jack M Fu
AU  - Isaac Wong
AU  - Michael E Talkowski
AU  - Manuel A Rivas
AU  - Floris Imhann
AU  - Laura Bolte
AU  - Hendrik van Dullemen
AU  - Gerard Dijkstra
AU  - Marijn C Visschedijk
AU  - Eleonora A Festen
AU  - Ramnik J Xavier
AU  - Jingyuan Fu
AU  - Mark J Daly
AU  - Cisca Wijmenga
AU  - Alexandra Zhernakova
AU  - Alexander Kurilshikov
AU  - Rinse K Weersma
TI  - Whole exome sequencing analyses reveal gene–microbiota interactions in the context of IBD
AID  - 10.1136/gutjnl-2019-319706
DP  - 2021 Feb 01
TA  - Gut
PG  - 285--296
VI  - 70
IP  - 2
4099  - http://gut.bmj.com/content/70/2/285.short
4100  - http://gut.bmj.com/content/70/2/285.full
SO  - Gut2021 Feb 01; 70
AB  - 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.