Application of the distance-based F test in an mGWAS investigating β diversity of intestinal microbiota identifies variants in SLC9A8 (NHE8) and 3 other loci

Abstract

Factors shaping the human intestinal microbiota range from environmental influences, like smoking and exercise, over dietary patterns and disease to the host's genetic variation. Recently, we could show in a microbiome genome-wide association study (mGWAS) targeting genetic variation influencing the β diversity of gut microbial communities, that approximately 10% of the overall gut microbiome variation can be explained by host genetics. Here, we report on the application of a new method for genotype-β-diversity association testing, the distance-based F (DBF) test. With this we identified 4 loci with genome-wide significant associations, harboring the genes CBEP4, SLC9A8, TNFSF4, and SP140, respectively. Our findings highlight the utility of the high-performance DBF test in β diversity GWAS and emphasize the important role of host genetics and immunity in shaping the human intestinal microbiota.

Keywords: GWAS; IBD; human gut microbiota; immunity; β diversity.

Figure 1.

Regional association plots of the β diversity meta-analysis. (A) TNFSF4/OX40L, Chromosome 1: 173Mb-173.4Mb, P_meta = 2.1 × 10⁻⁸; (B) SP140 and SP140L, Chromosome 2: 231Mb-231.4Mb, P_meta = 1.19 × 10⁻⁸; (C) CBEP4, Chromosome 5: 173.1Mb-173.5Mb, P_meta = 3.61 × 10⁻⁹; (D) SLC9A8/NHE8, Chromosome 20: 48.2Mb-48.7Mb, P_meta = 1.54 × 10⁻⁸.

Figure 2.

Comparison of the empirical distribution of ΔF from 10⁶ permutations of each of the 4 variants in both cohorts with probability density function approximated by using moment matching to Pearson Type III distribution. Red lines indicate the ΔF of the actual genotype distribution in the cohorts.