Genome-wide association studies in healthy first degree relatives (FDR) of Crohn’s Disease (CD) subjects reveal that host genetics polymorphisms are associated with the gut microbiota

Turpin, Williams

Wednesday, July 15, 2015

Grand Hall and Gallery, Ground Floor & 1st Floor (Maritim Hotel)

Williams Turpin , University of Toronto / Zane Cohen Centre for Digestive Diseases, Toronto, ON, Canada

Osvaldo Espin-Garcia , Lunenfeld-Tanenbaum Research Institute, Toronto, ON, Canada

Konstantin Shestopaloff , Dalla Lana School of Public Health, Toronto, ON, Canada

Lizhen Xu , Dalla Lana School of Public Health, Toronto, ON, Canada

Mark Silverberg , Mount Sinai Hospital, Toronto, ON, Canada

Michelle Smith , University of Toronto, Toronto, ON, Canada

Wei Xu , Dalla Lana School of Public Health, Toronto, ON, Canada

David Guttman , University of Toronto, Toronto, ON, Canada

Gabriel Moreno-Hagelsieb , Wilfrid Laurier University, Waterloo, ON, Canada

Andrew Paterson , The Hospital for Sick Children Research Institute, Toronto, ON, Canada

Ken Croitoru, MD , Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, ON, Canada

It has been suggested that inflammatory bowel disease (IBD) is due to a genetically determined abnormal interaction between gut immune responses and gut bacteria. In order to determine if the composition of gut microbiota is associated with host genetic makeup we assessed the stool microbiome in a cohort of 1098 FDRs of CD patients.

The V4 region of 16S rRNA gene was sequenced from bacterial DNA extracted from the stool of 1098 healthy Caucasian FDRs. MiSeq sequences were processed using PANDAseq and the QIIME pipeline. Polygenic heritability of the microbiota (H2R) was calculated from 271 related individuals using SOLAR software. Single nucleotide polymorphisms (SNPs) were determined with the HumanCoreExome BeadChip (Illumina). Associations between SNPs and microbiota were estimated using two-part log normal model fitted using generalized estimating equations and adjusting for age, sex, family structure and the first three genetic principal components.

A total of 91 out of 253 taxa show significant heritability (25%<H2R<67%, 0.05<H2R, p-value<3.2×10^-6). The taxa with highest heritability and/or the most abundant taxa were then assessed for association by a genome-wide scan containing 258,510 genetic markers. Several SNPs were significantly associated with microbial taxa (p<10-6). Fine mapping of regions showing significant associations will be required to identify the causal variant for these associations.

These results indicate that host genetics contribute to differences in intestinal microbiota composition in healthy subjects. It remains to be shown if any of these genetic/microbiome associations are related to the risk of developing Crohn’s disease.

Submitted on behalf of GEM project research team

ICMI 2015

W.104 Genome-wide association studies in healthy first degree relatives (FDR) of Crohn’s Disease (CD) subjects reveal that host genetics polymorphisms are associated with the gut microbiota