Abstract A31: Genome-wide association study (GWAS) of host DNA sequence variation and the gut microbiome in the Multiethnic Cohort
Authors: Hullar Meredith A. , Lampe Johanna W. , Randolph Timothy , Curtis Keith R. , Lim Unhee , Wilkens Lynne R. , Marchand Loic Le , Kristal Bruce S. , Monroe Kris R. , Zhao Kechen , Stram Daniel , Cheng Iona 
Published: December 2020

Abstract
Patterns of microbiome diversity vary across human populations, and although variation is largely driven by diet and lifestyle, genetically encoded differences between hosts may be important in shaping the microbiome and health outcomes, including cancer. We report preliminary results from a GWAS of the gut microbiome in 6,217 individuals from the Multiethnic Cohort Study, including African Americans, Japanese Americans, Native Hawaiians, Latinos, and Whites. Genome-wide SNP data was based on existing data from a variety of Illumina Infinium arrays (500,000 to 2.5 million single nucleotide polymorphisms (SNPs); n=4,363) as well as genotyping 1,853 individuals using the Illumina MEGA EX array. SNP imputation was conducted using a cosmopolitan reference panel of all 1000 Genomes samples. The stool microbiome was assessed by paired-end sequencing (Illumina MiSeq) of the16S rRNA gene (V1-3). SNP-genera association tests were conducted using linear regression of covariate-adjusted bacterial genera abundance quintiles on SNP genotype. The chi-square statistics were adjusted by the genomic inflation factor. A threshold of p=5 × 10−8 was used to determine genome-wide statistical significance. The covariate-adjusted genera values were computed as the residuals of a logistic ordinal regression of genera abundance quintiles on variables expected to affect the microbiome (i.e., age, sex, genetic ancestry proportions, sample month, and sequencing batch). Initial results yielded 22 genome-wide significant associations across SNPs in 15 different human chromosomes and 11 bacterial genera. Notably, Fusobacteria was significantly associated with star-related lipid transfer domain (STARD3, chromosome 13q13; p=2.8 × 10−8), voltage-dependent calcium channel gamma 3 subunit (CACNG3, chromosome 16p12; p=3.1 × 10−8), organic anion transporter polypeptide (OATP, SCLO2B1, chromosome 11q13; p=2.8 × 10−8), and E-cadherin (CDHR3, chromosome 7q22, p=1.6 × 10−8). Some Fusobacterial species have been associated with increased risk of colon tumors. Coprobacillus was significantly associated with ubiquitin modifier activating enzyme 2 (UBA2, chromosome 19q13, p=4.1 × 10−9). The pathogen Slackia was significantly associated with variants in the zinc finger 850 gene (ZNF850, chromosome 19p13; p=4.3 × 10−8). These results suggest that host gene variants may be important in shaping the microbiome and may influence bacterial pathogen-associated cancer outcomes.
Citation Format: Meredith A. Hullar, Johanna W. Lampe, Timothy Randolph, Keith R. Curtis, Unhee Lim, Lynne R. Wilkens, Loic Le Marchand, Bruce S. Kristal, Kris R. Monroe, Kechen Zhao, Daniel Stram, Iona Cheng. Genome-wide association study (GWAS) of host DNA sequence variation and the gut microbiome in the Multiethnic Cohort [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr A31.