Genome-wide association study (GWAS) of host germline variation and the gut microbiome: The Multiethnic Cohort Study

Abstract

Patterns of microbiome diversity vary across human populations largely driven by lifestyle and environmental factors. However, differences in genetically-encoded traits in the host may also be important in shaping the microbiome and related health outcomes. We report results from a GWAS of the gut microbiome in 5,202 individuals from the Multiethnic Cohort Study, including African American, Japanese American, Native Hawaiian, Latino, and White individuals. Genotyping was derived from previous studies (n = 3,337) using various Illumina Infinium arrays (660,000 to 2.5 million SNPs) and the MEGA EX array (n = 1,865). Single nucleotide polymorphism (SNP) imputation was conducted using a cosmopolitan reference panel from the 1000 Genomes Project. The stool microbiome was assessed by paired-end sequencing (Illumina MiSeq) of the16S rRNA gene (V1 − 3). SNP-genera association tests were conducted using ordinal logistic regression with quintiles of bacterial abundance regressed on SNPs, adjusted for age, ancestry estimates, season of sample collection, batch, and genotyping study, using a genome-wide statistical significance threshold of p < 5*10− 8. We identified associations between 53 SNPs in 11 human chromosomes and 16 bacterial/archaeal genera at p < 5*10− 8.The SNPs in coding regions were categorized into broad categories: human genes known to be exploited by bacterial pathogens; genes involved in nutrition, obesity, diabetes, and cancer; and immune function. Most significantly, Bifidobacterium abundance was associated with 2 known SNPs on chromosome 2 (rs182549 p = 3.8*10− 11; rs4988235 4.8*10− 11) in the MCM6 gene that were involved in lactose intolerance overall and in Latinos (rs182549 p = 4.12*10− 09 and rs4988235 p = 6.90*10− 09) and replicated in other studies. A significant association between Coriobacteriales and CDH18 (rs7701767,p = 1.5*10− 08) was also replicated in East Asian cohorts. Genetic variants in non-coding regions were primarily associated with host defenses against infection via solubilizing pathogen cell membranes, restricting growth of intracellular pathogens, and triggering inflammation though innate immune response. Fusicatenibacter was associated with a SNP (rs8067381,p = 1.63*10− 6) found in non-coding regions between SOCS7 and ARHGAP23 and replicated in several East Asian cohort. Expansion into human cohorts to include racial and ethnic diversity in host genetics and microbiome interactions to support an understanding of health outcomes across the human population.