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

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 ZhernakovaAlexander Kurilshikov, Rinse K Weersma^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
Article number	319706
Pages (from-to)	285-296
Number of pages	12
Journal	Gut
Volume	70
Issue number	2
Early online date	10-Jul-2020
DOIs	https://doi.org/10.1136/gutjnl-2019-319706
Publication status	Published - Feb-2021

Keywords

INFLAMMATORY-BOWEL-DISEASE
GENOME-WIDE ASSOCIATION
PROTEIN-COUPLED RECEPTORS
GUT MICROBIOME
HOST GENETICS
SUSCEPTIBILITY LOCI
VARIANTS
DETERMINANTS
ACTIVATION
FRAMEWORK

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Whole exome sequencing analyses reveal gene–microbiota interactions in the context of IBDFinal publisher's version, 1.67 MBLicence: CC BY

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Hu, S., Vich Vila, A., Gacesa, R., Collij, V., Stevens, C., Fu, J. M., Wong, I., Talkowski, M. E., Rivas, M. A., Imhann, F., Bolte, L., van Dullemen, H., Dijkstra, G., Visschedijk, M. C., Festen, E. A., Xavier, R. J., Fu, J., Daly, M. J., Wijmenga, C., ... Weersma, R. K. (2021). Whole exome sequencing analyses reveal gene-microbiota interactions in the context of IBD. Gut, 70(2), 285-296. [319706]. https://doi.org/10.1136/gutjnl-2019-319706

Hu, Shixian ; Vich Vila, Arnau ; Gacesa, Ranko ; Collij, Valerie ; Stevens, Christine ; Fu, Jack M ; Wong, Isaac ; Talkowski, Michael E ; Rivas, Manuel A ; Imhann, Floris ; Bolte, Laura ; van Dullemen, Hendrik ; Dijkstra, Gerard ; Visschedijk, Marijn C ; Festen, Eleonora A ; Xavier, Ramnik J ; Fu, Jingyuan ; Daly, Mark J ; Wijmenga, Cisca ; Zhernakova, Alexandra ; Kurilshikov, Alexander ; Weersma, Rinse K. / Whole exome sequencing analyses reveal gene-microbiota interactions in the context of IBD. In: Gut. 2021 ; Vol. 70, No. 2. pp. 285-296.

@article{a998b15e86844445931fa6bf6575f877,

title = "Whole exome sequencing analyses reveal gene-microbiota interactions in the context of IBD",

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 = "INFLAMMATORY-BOWEL-DISEASE, GENOME-WIDE ASSOCIATION, PROTEIN-COUPLED RECEPTORS, GUT MICROBIOME, HOST GENETICS, SUSCEPTIBILITY LOCI, VARIANTS, DETERMINANTS, ACTIVATION, FRAMEWORK",

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

note = "{\textcopyright} Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.",

year = "2021",

month = feb,

doi = "10.1136/gutjnl-2019-319706",

language = "English",

volume = "70",

pages = "285--296",

journal = "Gut",

issn = "0017-5749",

publisher = "BMJ PUBLISHING GROUP",

number = "2",

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Hu, S , Vich Vila, A , Gacesa, R , Collij, V, Stevens, C, Fu, JM, Wong, I, Talkowski, ME, Rivas, MA, Imhann, F , Bolte, L , van Dullemen, H , Dijkstra, G, Visschedijk, MC, Festen, EA, Xavier, RJ, Fu, J, Daly, MJ, Wijmenga, C , Zhernakova, A , Kurilshikov, A & Weersma, RK 2021, 'Whole exome sequencing analyses reveal gene-microbiota interactions in the context of IBD', Gut, vol. 70, no. 2, 319706, pp. 285-296. https://doi.org/10.1136/gutjnl-2019-319706

Whole exome sequencing analyses reveal gene-microbiota interactions in the context of IBD. / Hu, Shixian ; Vich Vila, Arnau ; Gacesa, Ranko ; Collij, Valerie; Stevens, Christine; Fu, Jack M; Wong, Isaac; Talkowski, Michael E; Rivas, Manuel A; Imhann, Floris ; Bolte, Laura ; van Dullemen, Hendrik ; Dijkstra, Gerard; Visschedijk, Marijn C; Festen, Eleonora A; Xavier, Ramnik J; Fu, Jingyuan; Daly, Mark J; Wijmenga, Cisca ; Zhernakova, Alexandra ; Kurilshikov, Alexander ; Weersma, Rinse K.

In: Gut, Vol. 70, No. 2, 319706, 02.2021, p. 285-296.

Research output: Contribution to journal › Article › Academic › peer-review

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

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 -