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

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

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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, …

Gastroenterology (New York, N.Y. 1943), Vol.151(4), pp.724-732

10/2016

DOI: https://doi.org/10.1053/j.gastro.2016.06.051

PMCID: PMC5037008

PMID: 27492617

Abstract

Genetics

Inflammatory Bowel Diseases

Microbiota

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). 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. 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). Our results suggest that an SLC39A8-dependent shift in the gut microbiome could explain its pleiotropic effects on multiple complex diseases including CD.

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Title: A Pleiotropic Missense Variant in SLC39A8 Is Associated With Crohn’s Disease and Human Gut Microbiome Composition
Creators: Dalin Li - F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California
Jean-Paul Achkar - Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio
Talin Haritunians - F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California
Jonathan P Jacobs - Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
Ken Y Hui - Division of Gastroenterology, Department of Medicine, Yale University, New Haven, Connecticut
Mauro D'Amato - Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
Stephan Brand - Department of Medicine II, University Hospital Munich-Grosshadern, Munich, Germany
Graham Radford-Smith - Inflammatory Bowel Diseases, Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia
Jonas Halfvarson - Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Orebro, Sweden
Jan-Hendrik Niess - Department of Internal Medicine I, University of Ulm, Ulm, Germany
Subra Kugathasan - Department of Pediatrics, Emory University School of Medicine and Children's Health Care of Atlanta, Atlanta, Georgia
Carsten Büning - Internal Medicine, Krankenhaus Waldfriede, Berlin, Germany
L. Philip Schumm - Department of Public Health Sciences, Biostatistical Laboratory, University of Chicago, Chicago, Illinois
Lambertus Klei - Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
Ashwin Ananthakrishnan - Gastroenterology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
Guy Aumais - Université de Montréal, Montréal, Québec, Canada
Leonard Baidoo - Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
Marla Dubinsky - F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California
Claudio Fiocchi - Pathobiology Department, Cleveland Clinic, Cleveland, Ohio
Jürgen Glas - Department of Preventive Dentistry and Periodontology, Ludwig-Maximilians-University, Munich, Germany
Raquel Milgrom - Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
Deborah D Proctor - Division of Gastroenterology, Department of Medicine, Yale University, New Haven, Connecticut
Miguel Regueiro - Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
Lisa A Simms - Inflammatory Bowel Diseases, Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia
Joanne M Stempak - Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
Stephan R Targan - F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California
Leif Törkvist - Department of Clinical Science Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
Yashoda Sharma - Department of Genetic & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
Bernie Devlin - Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
James Borneman - Department of Plant Pathology and Microbiology, University of California, Riverside, Riverside, California
Hakon Hakonarson - Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
Ramnik J Xavier - Gastroenterology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
Mark Daly - Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
Steven R Brant - Division of Gastroenterology and Hepatology, School of Medicine, Johns Hopkins University, Baltimore, Maryland
John D Rioux - Université de Montréal, Montréal, Québec, Canada
Mark S Silverberg - Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
Judy H Cho - Department of Genetic & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
Jonathan Braun - Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
Dermot P.B McGovern - F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California
Richard H Duerr - Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
Publication Details: Gastroenterology (New York, N.Y. 1943), Vol.151(4), pp.724-732
Date published: 10/2016
Publisher: Elsevier Inc
Academic Unit: Medicine - Gastroenterology and Hepatology (RWJMS)
Language: English
Resource Type: Journal article
Identifiers: 991031665012504646