A Pleiotropic Missense Variant in SLC39A8 Is Associated With Crohn's Disease and Human Gut Microbiome Composition

Dalin Li; Jean Paul Achkar; Talin Haritunians; Jonathan P. Jacobs; Ken Y. Hui; Mauro D'Amato; Stephan Brand; Graham Radford-Smith; Jonas Halfvarson; Jan Hendrik Niess; Subra Kugathasan; Carsten Büning; L. Philip Schumm; Lambertus Klei; Ashwin Ananthakrishnan; Guy Aumais; Leonard Baidoo; Marla Dubinsky; Claudio Fiocchi; Jürgen Glas; Raquel Milgrom; Deborah D. Proctor; Miguel Regueiro; Lisa A. Simms; Joanne M. Stempak; Stephan R. Targan; Leif Törkvist; Yashoda Sharma; Bernie Devlin; James Borneman; Hakon Hakonarson; Ramnik J. Xavier; Mark Daly; Steven R. Brant; John D. Rioux; Mark S. Silverberg; Judy H. Cho; Jonathan Braun; Dermot P B McGovern; Richard H. Duerr

doi:10.1053/j.gastro.2016.06.051

A Pleiotropic Missense Variant in SLC39A8 Is Associated With Crohn's Disease and Human Gut Microbiome Composition

Dalin Li, Jean Paul Achkar, Talin Haritunians, Jonathan P. Jacobs, Ken Y. Hui, Mauro D'Amato, Stephan Brand, Graham Radford-Smith, Jonas Halfvarson, Jan Hendrik Niess, Subra Kugathasan, Carsten Büning, L. Philip Schumm, Lambertus Klei, Ashwin Ananthakrishnan, Guy Aumais, Leonard Baidoo, Marla Dubinsky, Claudio Fiocchi, Jürgen GlasRaquel Milgrom, Deborah D. Proctor, Miguel Regueiro, Lisa A. Simms, Joanne M. Stempak, Stephan R. Targan, Leif Törkvist, Yashoda Sharma, Bernie Devlin, James Borneman, Hakon Hakonarson, Ramnik J. Xavier, Mark Daly, Steven R. Brant, John D. Rioux, Mark S. Silverberg, Judy H. Cho, Jonathan Braun, Dermot P B McGovern, Richard H. Duerr^*

^*Corresponding author for this work

Medicine, Gastroenterology Division

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

107 Scopus citations

Abstract

Background & Aims Genome-wide association studies have identified 200 inflammatory bowel disease (IBD) loci, but the genetic architecture of Crohn's disease (CD) and ulcerative colitis remain incompletely defined. Here, we aimed to identify novel associations between IBD and functional genetic variants using the Illumina ExomeChip (San Diego, CA). Methods Genotyping was performed in 10,523 IBD cases and 5726 non-IBD controls. There were 91,713 functional single-nucleotide polymorphism loci in coding regions analyzed. A novel identified association was replicated further in 2 independent cohorts. We further examined the association of the identified single-nucleotide polymorphism with microbiota from 338 mucosal lavage samples in the Mucosal Luminal Interface cohort measured using 16S sequencing. Results We identified an association between CD and a missense variant encoding alanine or threonine at position 391 in the zinc transporter solute carrier family 39, member 8 protein (SLC39A8 alanine 391 threonine, rs13107325) and replicated the association with CD in 2 replication cohorts (combined meta-analysis P = 5.55 × 10^-13). This variant has been associated previously with distinct phenotypes including obesity, lipid levels, blood pressure, and schizophrenia. We subsequently determined that the CD risk allele was associated with altered colonic mucosal microbiome composition in both healthy controls (P =.009) and CD cases (P =.0009). Moreover, microbes depleted in healthy carriers strongly overlap with those reduced in CD patients (P = 9.24 × 10^-16) and overweight individuals (P = 6.73 × 10^-16). Conclusions Our results suggest that an SLC39A8-dependent shift in the gut microbiome could explain its pleiotropic effects on multiple complex diseases including CD.

Original language	English (US)
Pages (from-to)	724-732
Number of pages	9
Journal	Gastroenterology
Volume	151
Issue number	4
DOIs	https://doi.org/10.1053/j.gastro.2016.06.051
State	Published - Oct 1 2016

Funding

Funding Funding for this work is acknowledged by the authors whose initials or names are in parentheses following each source of support. The National Institute of Diabetes and Digestive and Kidney Diseases Inflammatory Bowel Disease Genetics Consortium is supported by National Institutes of Health grants U01DK062413 (D.P.B.M. and J.Br.), U01DK062420 (R.H.D. and M.D.R.), U01DK062422 (J.H.C., K.Y.H., and D.D.P.), U01DK062429 (J.H.C., L.P.S., and Y.S.), U01DK062423 (M.S.S., R.M., and J.M.S.), U01DK062431 (S.R.B.), and U01DK062432 (J.D.R.). This work also was supported by National Institutes of Health grants F30DK098927 (K.Y.H.), P01DK046763 (S.R.T., J.Br., and D.P.B.M.), P30CA016042 (J.Br.), R01CA141743 (R.H.D.), R01DK087694 (S.K.), R01DK092235 (J.H.C. and K.Y.H.), R01DK098231 (S.K.), R01HS021747 (D.P.B.M.), T32DK007180 (J.P.J.), T32GM007205 (K.Y.H.), U01AI067068 (D.P.B.M.), U54DE023798 (J.Br.), and UL1TR000124 (J.Br.). Additional sources of support included the Crohn\u2019s and Colitis Foundation of America (J.Br. and H.H.), Deutsche Forschungsgemeinschaft (DFG BR 1912/6-1) (S.R.B.), Deutsche Forschungsgemeinschaft (projects Ni575/7-1 and Ni 575/4-1) (J.-H.N.), Else Kr\u00F6ner-Fresenius-Stiftung (Else Kr\u00F6ner Exzellenzstipendium 2010; 2010_EKES.32) (S.R.B.), Inflammatory Bowel Disease Genetic Research Chair at the University of Pittsburgh (R.H.D.), Institutional Development Fund from The Children's Hospital of Philadelphia (H.H.), \u00D6rebro University Hospital Research Foundation (J.H.), Royal Brisbane and Women\u2019s Hospital Research Foundation (G.R.-S.), Sanford J Grossman Charitable Trust (J.H.C.), SUCCESS (J.H.C.), Swedish Research Council grants 521-2011-2764 (J.H.), VR 2010-2976 (M.D.), and VR 2013-3862) (M.D.), Swiss National Science Foundation 146290 (J.-H.N.), The Eli and Edythe Broad Foundation, proposal IBD-0164R (C.B.), The European Union (D.P.B.M.), The Kenneth Rainin Chair for Inflammatory Bowel Disease Research (J.-P.A.), The Leona M and Harry B Helmsley Charitable Trust (D.P.B.M.), and The National Health and Medical Research Council (APP498405) (G.R.-S.). The authors thank the following investigators for providing additional control samples: M. Ilyas Kamboh with support from National Institutes of Health grants R01AG030653, R01AG041718, P50AG005133, R01AG007562, and R01AG023651; David C. Whitcomb with support from National Institutes of Health grant R01DK061451; Todd Lencz; and Peter K. Gregersen.

Keywords

Genetics
Inflammatory Bowel Diseases
Microbiota

ASJC Scopus subject areas

Hepatology
Gastroenterology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1053/j.gastro.2016.06.051

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Li, D., Achkar, J. P., Haritunians, T., Jacobs, J. P., Hui, K. Y., D'Amato, M., Brand, S., Radford-Smith, G., Halfvarson, J., Niess, J. H., Kugathasan, S., Büning, C., Schumm, L. P., Klei, L., Ananthakrishnan, A., Aumais, G., Baidoo, L., Dubinsky, M., Fiocchi, C., ... Duerr, R. H. (2016). A Pleiotropic Missense Variant in SLC39A8 Is Associated With Crohn's Disease and Human Gut Microbiome Composition. Gastroenterology, 151(4), 724-732. https://doi.org/10.1053/j.gastro.2016.06.051

@article{439156cb8e3f4c049d8f739c2dac394c,

title = "A Pleiotropic Missense Variant in SLC39A8 Is Associated With Crohn's Disease and Human Gut Microbiome Composition",

abstract = "Background & Aims Genome-wide association studies have identified 200 inflammatory bowel disease (IBD) loci, but the genetic architecture of Crohn's disease (CD) and ulcerative colitis remain incompletely defined. Here, we aimed to identify novel associations between IBD and functional genetic variants using the Illumina ExomeChip (San Diego, CA). Methods Genotyping was performed in 10,523 IBD cases and 5726 non-IBD controls. There were 91,713 functional single-nucleotide polymorphism loci in coding regions analyzed. A novel identified association was replicated further in 2 independent cohorts. We further examined the association of the identified single-nucleotide polymorphism with microbiota from 338 mucosal lavage samples in the Mucosal Luminal Interface cohort measured using 16S sequencing. Results We identified an association between CD and a missense variant encoding alanine or threonine at position 391 in the zinc transporter solute carrier family 39, member 8 protein (SLC39A8 alanine 391 threonine, rs13107325) and replicated the association with CD in 2 replication cohorts (combined meta-analysis P = 5.55 × 10-13). This variant has been associated previously with distinct phenotypes including obesity, lipid levels, blood pressure, and schizophrenia. We subsequently determined that the CD risk allele was associated with altered colonic mucosal microbiome composition in both healthy controls (P =.009) and CD cases (P =.0009). Moreover, microbes depleted in healthy carriers strongly overlap with those reduced in CD patients (P = 9.24 × 10-16) and overweight individuals (P = 6.73 × 10-16). Conclusions Our results suggest that an SLC39A8-dependent shift in the gut microbiome could explain its pleiotropic effects on multiple complex diseases including CD.",

keywords = "Genetics, Inflammatory Bowel Diseases, Microbiota",

author = "Dalin Li and Achkar, {Jean Paul} and Talin Haritunians and Jacobs, {Jonathan P.} and Hui, {Ken Y.} and Mauro D'Amato and Stephan Brand and Graham Radford-Smith and Jonas Halfvarson and Niess, {Jan Hendrik} and Subra Kugathasan and Carsten B{\"u}ning and Schumm, {L. Philip} and Lambertus Klei and Ashwin Ananthakrishnan and Guy Aumais and Leonard Baidoo and Marla Dubinsky and Claudio Fiocchi and J{\"u}rgen Glas and Raquel Milgrom and Proctor, {Deborah D.} and Miguel Regueiro and Simms, {Lisa A.} and Stempak, {Joanne M.} and Targan, {Stephan R.} and Leif T{\"o}rkvist and Yashoda Sharma and Bernie Devlin and James Borneman and Hakon Hakonarson and Xavier, {Ramnik J.} and Mark Daly and Brant, {Steven R.} and Rioux, {John D.} and Silverberg, {Mark S.} and Cho, {Judy H.} and Jonathan Braun and McGovern, {Dermot P B} and Duerr, {Richard H.}",

note = "Publisher Copyright: {\textcopyright} 2016 AGA Institute",

year = "2016",

month = oct,

day = "1",

doi = "10.1053/j.gastro.2016.06.051",

language = "English (US)",

volume = "151",

pages = "724--732",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "W.B. Saunders",

number = "4",

}

Li, D, Achkar, JP, Haritunians, T, Jacobs, JP, Hui, KY, D'Amato, M, Brand, S, Radford-Smith, G, Halfvarson, J, Niess, JH, Kugathasan, S, Büning, C, Schumm, LP, Klei, L, Ananthakrishnan, A, Aumais, G, Baidoo, L, Dubinsky, M, Fiocchi, C, Glas, J, Milgrom, R, Proctor, DD, Regueiro, M, Simms, LA, Stempak, JM, Targan, SR, Törkvist, L, Sharma, Y, Devlin, B, Borneman, J, Hakonarson, H, Xavier, RJ, Daly, M, Brant, SR, Rioux, JD, Silverberg, MS, Cho, JH, Braun, J, McGovern, DPB & Duerr, RH 2016, 'A Pleiotropic Missense Variant in SLC39A8 Is Associated With Crohn's Disease and Human Gut Microbiome Composition', Gastroenterology, vol. 151, no. 4, pp. 724-732. https://doi.org/10.1053/j.gastro.2016.06.051

TY - JOUR

T1 - A Pleiotropic Missense Variant in SLC39A8 Is Associated With Crohn's Disease and Human Gut Microbiome Composition

AU - Li, Dalin

AU - Achkar, Jean Paul

AU - Haritunians, Talin

AU - Jacobs, Jonathan P.

AU - Hui, Ken Y.

AU - D'Amato, Mauro

AU - Brand, Stephan

AU - Radford-Smith, Graham

AU - Halfvarson, Jonas

AU - Niess, Jan Hendrik

AU - Kugathasan, Subra

AU - Büning, Carsten

AU - Schumm, L. Philip

AU - Klei, Lambertus

AU - Ananthakrishnan, Ashwin

AU - Aumais, Guy

AU - Baidoo, Leonard

AU - Dubinsky, Marla

AU - Fiocchi, Claudio

AU - Glas, Jürgen

AU - Milgrom, Raquel

AU - Proctor, Deborah D.

AU - Regueiro, Miguel

AU - Simms, Lisa A.

AU - Stempak, Joanne M.

AU - Targan, Stephan R.

AU - Törkvist, Leif

AU - Sharma, Yashoda

AU - Devlin, Bernie

AU - Borneman, James

AU - Hakonarson, Hakon

AU - Xavier, Ramnik J.

AU - Daly, Mark

AU - Brant, Steven R.

AU - Rioux, John D.

AU - Silverberg, Mark S.

AU - Cho, Judy H.

AU - Braun, Jonathan

AU - McGovern, Dermot P B

AU - Duerr, Richard H.

PY - 2016/10/1

Y1 - 2016/10/1

N2 - Background & Aims Genome-wide association studies have identified 200 inflammatory bowel disease (IBD) loci, but the genetic architecture of Crohn's disease (CD) and ulcerative colitis remain incompletely defined. Here, we aimed to identify novel associations between IBD and functional genetic variants using the Illumina ExomeChip (San Diego, CA). Methods Genotyping was performed in 10,523 IBD cases and 5726 non-IBD controls. There were 91,713 functional single-nucleotide polymorphism loci in coding regions analyzed. A novel identified association was replicated further in 2 independent cohorts. We further examined the association of the identified single-nucleotide polymorphism with microbiota from 338 mucosal lavage samples in the Mucosal Luminal Interface cohort measured using 16S sequencing. Results We identified an association between CD and a missense variant encoding alanine or threonine at position 391 in the zinc transporter solute carrier family 39, member 8 protein (SLC39A8 alanine 391 threonine, rs13107325) and replicated the association with CD in 2 replication cohorts (combined meta-analysis P = 5.55 × 10-13). This variant has been associated previously with distinct phenotypes including obesity, lipid levels, blood pressure, and schizophrenia. We subsequently determined that the CD risk allele was associated with altered colonic mucosal microbiome composition in both healthy controls (P =.009) and CD cases (P =.0009). Moreover, microbes depleted in healthy carriers strongly overlap with those reduced in CD patients (P = 9.24 × 10-16) and overweight individuals (P = 6.73 × 10-16). Conclusions Our results suggest that an SLC39A8-dependent shift in the gut microbiome could explain its pleiotropic effects on multiple complex diseases including CD.

AB - Background & Aims Genome-wide association studies have identified 200 inflammatory bowel disease (IBD) loci, but the genetic architecture of Crohn's disease (CD) and ulcerative colitis remain incompletely defined. Here, we aimed to identify novel associations between IBD and functional genetic variants using the Illumina ExomeChip (San Diego, CA). Methods Genotyping was performed in 10,523 IBD cases and 5726 non-IBD controls. There were 91,713 functional single-nucleotide polymorphism loci in coding regions analyzed. A novel identified association was replicated further in 2 independent cohorts. We further examined the association of the identified single-nucleotide polymorphism with microbiota from 338 mucosal lavage samples in the Mucosal Luminal Interface cohort measured using 16S sequencing. Results We identified an association between CD and a missense variant encoding alanine or threonine at position 391 in the zinc transporter solute carrier family 39, member 8 protein (SLC39A8 alanine 391 threonine, rs13107325) and replicated the association with CD in 2 replication cohorts (combined meta-analysis P = 5.55 × 10-13). This variant has been associated previously with distinct phenotypes including obesity, lipid levels, blood pressure, and schizophrenia. We subsequently determined that the CD risk allele was associated with altered colonic mucosal microbiome composition in both healthy controls (P =.009) and CD cases (P =.0009). Moreover, microbes depleted in healthy carriers strongly overlap with those reduced in CD patients (P = 9.24 × 10-16) and overweight individuals (P = 6.73 × 10-16). Conclusions Our results suggest that an SLC39A8-dependent shift in the gut microbiome could explain its pleiotropic effects on multiple complex diseases including CD.

KW - Genetics

KW - Inflammatory Bowel Diseases

KW - Microbiota

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U2 - 10.1053/j.gastro.2016.06.051

DO - 10.1053/j.gastro.2016.06.051

M3 - Article

C2 - 27492617

AN - SCOPUS:84989894301

SN - 0016-5085

VL - 151

SP - 724

EP - 732

JO - Gastroenterology

JF - Gastroenterology

IS - 4

ER -

A Pleiotropic Missense Variant in SLC39A8 Is Associated With Crohn's Disease and Human Gut Microbiome Composition

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UN SDGs

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