title: A Pleiotropic Missense Variant in SLC39A8 Is Associated With Crohn's Disease and Human Gut Microbiome Composition.
abstract: 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.
authors: F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California.
authors: Dalin
authors: D
authors: Li
authors: Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio.
authors: Jean-Paul
authors: JP
authors: Achkar
authors: F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California.
authors: Talin
authors: T
authors: Haritunians
authors: Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
authors: Jonathan P
authors: JP
authors: Jacobs
authors: Division of Gastroenterology, Department of Medicine, Yale University, New Haven, Connecticut.
authors: Ken Y
authors: KY
authors: Hui
authors: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden; Biocruces Health Research Institute, Barakaldo, Bizkaia, Spain.
authors: Mauro
authors: M
authors: D'Amato
authors: Department of Medicine II, University Hospital Munich-Grosshadern, Munich, Germany.
authors: Stephan
authors: S
authors: Brand
authors: Inflammatory Bowel Diseases, Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia; Department of Gastroenterology, Royal Brisbane and Women's Hospital, Brisbane, Australia; School of Medicine, University of Queensland, Brisbane, Australia.
authors: Graham
authors: G
authors: Radford-Smith
authors: Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Orebro, Sweden.
authors: Jonas
authors: J
authors: Halfvarson
authors: Department of Internal Medicine I, University of Ulm, Ulm, Germany; Division of Visceral Surgery and Medicine, Department of Gastroenterology, Inselspital Bern, Bern, Switzerland; Gastroenterology and Hepatology, University Hospital Basel, Basel, Switzerland.
authors: Jan-Hendrik
authors: JH
authors: Niess
authors: Department of Pediatrics, Emory University School of Medicine and Children's Health Care of Atlanta, Atlanta, Georgia.
authors: Subra
authors: S
authors: Kugathasan
authors: Internal Medicine, Krankenhaus Waldfriede, Berlin, Germany.
authors: Carsten
authors: C
authors: Büning
authors: Department of Public Health Sciences, Biostatistical Laboratory, University of Chicago, Chicago, Illinois.
authors: L Philip
authors: LP
authors: Schumm
authors: Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors: Lambertus
authors: L
authors: Klei
authors: Gastroenterology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors: Ashwin
authors: A
authors: Ananthakrishnan
authors: Université de Montréal, Montréal, Québec, Canada; Hopital Maisonneuve Rosemont, Montréal, Québec, Canada.
authors: Guy
authors: G
authors: Aumais
authors: Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors: Leonard
authors: L
authors: Baidoo
authors: F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York.
authors: Marla
authors: M
authors: Dubinsky
authors: Pathobiology Department, Cleveland Clinic, Cleveland, Ohio.
authors: Claudio
authors: C
authors: Fiocchi
authors: Department of Preventive Dentistry and Periodontology, Ludwig-Maximilians-University, Munich, Germany.
authors: Jürgen
authors: J
authors: Glas
authors: Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
authors: Raquel
authors: R
authors: Milgrom
authors: Division of Gastroenterology, Department of Medicine, Yale University, New Haven, Connecticut.
authors: Deborah D
authors: DD
authors: Proctor
authors: Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors: Miguel
authors: M
authors: Regueiro
authors: Inflammatory Bowel Diseases, Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors: Lisa A
authors: LA
authors: Simms
authors: Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
authors: Joanne M
authors: JM
authors: Stempak
authors: F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California.
authors: Stephan R
authors: SR
authors: Targan
authors: Department of Clinical Science Intervention and Technology, Karolinska Institutet, Stockholm, Sweden; Center for Digestive Disease, IBD-unit, Karolinska University Hospital, Stockholm, Sweden.
authors: Leif
authors: L
authors: Törkvist
authors: Department of Genetic & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors: Yashoda
authors: Y
authors: Sharma
authors: Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors: Bernie
authors: B
authors: Devlin
authors: Department of Plant Pathology and Microbiology, University of California, Riverside, Riverside, California.
authors: James
authors: J
authors: Borneman
authors: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors: Hakon
authors: H
authors: Hakonarson
authors: Gastroenterology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
authors: Ramnik J
authors: RJ
authors: Xavier
authors: Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors: Mark
authors: M
authors: Daly
authors: Division of Gastroenterology and Hepatology, School of Medicine, Johns Hopkins University, Baltimore, Maryland; Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland.
authors: Steven R
authors: SR
authors: Brant
authors: Université de Montréal, Montréal, Québec, Canada; Montreal Heart Institute, Montréal, Québec, Canada.
authors: John D
authors: JD
authors: Rioux
authors: Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
authors: Mark S
authors: MS
authors: Silverberg
authors: Department of Genetic & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
authors: Judy H
authors: JH
authors: Cho
authors: Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
authors: Jonathan
authors: J
authors: Braun
authors: F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California.
authors: Dermot P B
authors: DP
authors: McGovern
authors: Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania. Electronic address: duerr@pitt.edu.
authors: Richard H
authors: RH
authors: Duerr
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D027682:Cation Transport Proteins / Q000235:genetics*; D003093:Colitis, Ulcerative / Q000235:genetics* / Q000382:microbiology; D003424:Crohn Disease / Q000235:genetics* / Q000382:microbiology; D005260:Female; D000069196:Gastrointestinal Microbiome / Q000235:genetics*; D058685:Genetic Pleiotropy; D005838:Genotype; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D012307:Risk Factors
chemical_list: D027682:Cation Transport Proteins; C530151:SLC39A8 protein, human
keywords: Genetics; Inflammatory Bowel Diseases; Microbiota