title: Complex host genetics influence the microbiome in inflammatory bowel disease.
abstract: BACKGROUND
  Human genetics and host-associated microbial communities have been associated independently with a wide range of chronic diseases. One of the strongest associations in each case is inflammatory bowel disease (IBD), but disease risk cannot be explained fully by either factor individually. Recent findings point to interactions between host genetics and microbial exposures as important contributors to disease risk in IBD. These include evidence of the partial heritability of the gut microbiota and the conferral of gut mucosal inflammation by microbiome transplant even when the dysbiosis was initially genetically derived. Although there have been several tests for association of individual genetic loci with bacterial taxa, there has been no direct comparison of complex genome-microbiome associations in large cohorts of patients with an immunity-related disease.
  
  
  METHODS
  We obtained 16S ribosomal RNA (rRNA) gene sequences from intestinal biopsies as well as host genotype via Immunochip in three independent cohorts totaling 474 individuals. We tested for correlation between relative abundance of bacterial taxa and number of minor alleles at known IBD risk loci, including fine mapping of multiple risk alleles in the Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) gene exon. We identified host polymorphisms whose associations with bacterial taxa were conserved across two or more cohorts, and we tested related genes for enrichment of host functional pathways.
  
  
  RESULTS
  We identified and confirmed in two cohorts a significant association between NOD2 risk allele count and increased relative abundance of Enterobacteriaceae, with directionality of the effect conserved in the third cohort. Forty-eight additional IBD-related SNPs have directionality of their associations with bacterial taxa significantly conserved across two or three cohorts, implicating genes enriched for regulation of innate immune response, the JAK-STAT cascade, and other immunity-related pathways.
  
  
  CONCLUSIONS
  These results suggest complex interactions between genetically altered host functional pathways and the structure of the microbiome. Our findings demonstrate the ability to uncover novel associations from paired genome-microbiome data, and they suggest a complex link between host genetics and microbial dysbiosis in subjects with IBD across independent cohorts.
authors.affiliation: Department of Computer Science and Engineering, University of Minnesota, Minneapolis, Minnesota 55455 USA ; Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142 USA ; Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114 USA ; Biotechnology Institute, University of Minnesota, St. Paul, Minnesota 55108 USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Knights
authors.affiliation: Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital IBD Group, University of Toronto, Toronto, Ontario M5G 1X5 Canada.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Silverberg
authors.affiliation: Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, 9700RB The Netherlands.
authors.forename: Rinse K
authors.initials: RK
authors.lastname: Weersma
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142 USA.
authors.forename: Dirk
authors.initials: D
authors.lastname: Gevers
authors.affiliation: Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, 9700RB The Netherlands.
authors.forename: Gerard
authors.initials: G
authors.lastname: Dijkstra
authors.affiliation: Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114 USA.
authors.forename: Hailiang
authors.initials: H
authors.lastname: Huang
authors.affiliation: Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital IBD Group, University of Toronto, Toronto, Ontario M5G 1X5 Canada.
authors.forename: Andrea D
authors.initials: AD
authors.lastname: Tyler
authors.affiliation: Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, 9700RB The Netherlands ; Department of Genetics, University Medical Center Groningen, Groningen, 9700RB The Netherlands.
authors.forename: Suzanne
authors.initials: S
authors.lastname: van Sommeren
authors.affiliation: Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, 9700RB The Netherlands ; Department of Genetics, University Medical Center Groningen, Groningen, 9700RB The Netherlands.
authors.forename: Floris
authors.initials: F
authors.lastname: Imhann
authors.affiliation: Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital IBD Group, University of Toronto, Toronto, Ontario M5G 1X5 Canada.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Stempak
authors.affiliation: Biomedical Informatics and Computational Biology, University of Minnesota, Minneapolis, Minnesota 55455 USA.
authors.forename: Hu
authors.initials: H
authors.lastname: Huang
authors.affiliation: Biomedical Informatics and Computational Biology, University of Minnesota, Minneapolis, Minnesota 55455 USA.
authors.forename: Pajau
authors.initials: P
authors.lastname: Vangay
authors.affiliation: Biomedical Informatics and Computational Biology, University of Minnesota, Minneapolis, Minnesota 55455 USA.
authors.forename: Gabriel A
authors.initials: GA
authors.lastname: Al-Ghalith
authors.affiliation: Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114 USA ; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114 USA.
authors.forename: Caitlin
authors.initials: C
authors.lastname: Russell
authors.affiliation: Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114 USA.
authors.forename: Jenny
authors.initials: J
authors.lastname: Sauk
authors.affiliation: Department of Psychiatry, University of Toronto, Toronto, Ontario M5T 1R8 Canada.
authors.forename: Jo
authors.initials: J
authors.lastname: Knight
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142 USA ; Department of Medicine, Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114 USA ; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142 USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142 USA ; Biostatistics Department, Harvard School of Public Health, Boston, Massachusetts 02115 USA.
authors.forename: Curtis
authors.initials: C
authors.lastname: Huttenhower
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142 USA ; Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114 USA ; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114 USA.
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier