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Kernel-based genetic association analysis for microbiome phenotypes identifies host genetic drivers of beta-diversity.

TitleKernel-based genetic association analysis for microbiome phenotypes identifies host genetic drivers of beta-diversity.
Publication TypePublication
AuthorsLiu H, Ling W, Hua X, Moon J-Y, Williams-Nguyen JS, Zhan X, Plantinga AM, Zhao N, Zhang A, Knight R, Qi Q, Burk RD, Kaplan RC, Wu MC
Date Published2023 Apr 20
KeywordsComputer Simulation, Gastrointestinal Microbiome, genome-wide association study, Humans, Microbiota, Phenotype

BACKGROUND: Understanding human genetic influences on the gut microbiota helps elucidate the mechanisms by which genetics may influence health outcomes. Typical microbiome genome-wide association studies (GWAS) marginally assess the association between individual genetic variants and individual microbial taxa. We propose a novel approach, the covariate-adjusted kernel RV (KRV) framework, to map genetic variants associated with microbiome beta-diversity, which focuses on overall shifts in the microbiota. The KRV framework evaluates the association between genetics and microbes by comparing similarity in genetic profiles, based on groups of variants at the gene level, to similarity in microbiome profiles, based on the overall microbiome composition, across all pairs of individuals. By reducing the multiple-testing burden and capturing intrinsic structure within the genetic and microbiome data, the KRV framework has the potential of improving statistical power in microbiome GWAS.RESULTS: We apply the covariate-adjusted KRV to the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) in a two-stage (first gene-level, then variant-level) genome-wide association analysis for gut microbiome beta-diversity. We have identified an immunity-related gene, IL23R, reported in a previous microbiome genetic association study and discovered 3 other novel genes, 2 of which are involved in immune functions or autoimmune disorders. In addition, simulation studies show that the covariate-adjusted KRV has a greater power than other microbiome GWAS methods that rely on univariate microbiome phenotypes across a range of scenarios.CONCLUSIONS: Our findings highlight the value of the covariate-adjusted KRV as a powerful microbiome GWAS approach and support an important role of immunity-related genes in shaping the gut microbiome composition. Video Abstract.

Alternate JournalMicrobiome
PubMed ID37081571
PubMed Central IDPMC10116795
Grant ListR01 GM129512 / GM / NIGMS NIH HHS / United States
1R01MD011389-01 / NH / NIH HHS / United States
R01GM129512 / NH / NIH HHS / United States
Manuscript Lead/Corresponding Author Affiliation: 
Affiliated Investigator - Not at HCHS/SOL site
Manuscript Affiliation: 
Field Center: Bronx (Einstein College of Medicine)
Manuscript Status: