TY - JOUR
T1 - Whole exome sequencing analyses reveal gene-microbiota interactions in the context of IBD
AU - Hu, Shixian
AU - Vich Vila, Arnau
AU - Gacesa, Ranko
AU - Collij, Valerie
AU - Stevens, Christine
AU - Fu, Jack M
AU - Wong, Isaac
AU - Talkowski, Michael E
AU - Rivas, Manuel A
AU - Imhann, Floris
AU - Bolte, Laura
AU - van Dullemen, Hendrik
AU - Dijkstra, Gerard
AU - Visschedijk, Marijn C
AU - Festen, Eleonora A
AU - Xavier, Ramnik J
AU - Fu, Jingyuan
AU - Daly, Mark J
AU - Wijmenga, Cisca
AU - Zhernakova, Alexandra
AU - Kurilshikov, Alexander
AU - Weersma, Rinse K
N1 - © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.
PY - 2021/2
Y1 - 2021/2
N2 - 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.
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.
KW - INFLAMMATORY-BOWEL-DISEASE
KW - GENOME-WIDE ASSOCIATION
KW - PROTEIN-COUPLED RECEPTORS
KW - GUT MICROBIOME
KW - HOST GENETICS
KW - SUSCEPTIBILITY LOCI
KW - VARIANTS
KW - DETERMINANTS
KW - ACTIVATION
KW - FRAMEWORK
U2 - 10.1136/gutjnl-2019-319706
DO - 10.1136/gutjnl-2019-319706
M3 - Article
C2 - 32651235
VL - 70
SP - 285
EP - 296
JO - Gut
JF - Gut
SN - 0017-5749
IS - 2
M1 - 319706
ER -