A genome-wide association study for gut metagenome in Chinese adults illuminates complex diseases

Abstract

The gut microbiome has been established as a key environmental factor to health. Genetic influences on the gut microbiome have been reported, yet, doubts remain as to the significance of genetic associations. Here, we provide shotgun data for whole genome and whole metagenome from a Chinese cohort, identifying no <20% genetic contribution to the gut microbiota. Using common variants-, rare variants-, and copy number variations-based association analyses, we identified abundant signals associated with the gut microbiome especially in metabolic, neurological, and immunological functions. The controversial concept of enterotypes may have a genetic attribute, with the top two loci explaining 11% of the Prevotella–Bacteroides variances. Stratification according to gender led to the identification of differential associations in males and females. Our two-stage metagenome genome-wide association studies on a total of 1295 individuals unequivocally illustrates that neither microbiome nor GWAS studies could overlook one another in our quest for a better understanding of human health and diseases.

Metagenome-genome-wide association studies reveal human genetic impact on the oral microbiome

“…in China. The protocols for blood and oral collection, as well as the whole genome and metagenomic sequencing were similar to our previous literature 5,23,48 . For blood sample, DNA was extracted using MagPure Buffy Coat DNA Midi KF Kit (no.…”

“…3,932 (2,017 tongue dorsum and 1,915 saliva) oral samples from this cohort were newly collected for whole metagenomic sequencing between 2017 to 2018 ( Supplementary Table 1 ). The protocols for blood and oral collection, as well as the whole genome and metagenomic sequencing were similar to our previous literature 5,23,42 . For blood sample, DNA was extracted using MagPure Buffy Coat DNA Midi KF Kit (no.…”

“…A health individual swallows 1-1.5 liters of saliva every day 1 , the microbes in which could colonize the gut of susceptible individuals 2-5 . Oral metagenomic shotgun sequencing data has been available from the Human Microbiome Project (HMP) 6 , for rheumatoid arthritis 7 and colorectal cancer 3 .…”

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

“…In our gene-level analysis using the PC-adjusted KRV, the LCT gene is nominally significant based on the unweighted UniFrac kernel (p-value = 0.013), but not significant at the genome-wide level. In addition, we have examined the significance of 63 previously reported genes that harbor variants associated with microbiome beta-diversity [10,12,14,39,40] (Supplementary Table S3). orating the role of immunity-related genes in shaping gut microbiota.…”

“…These approaches still test one variant at a time and are subject to a stringent genome-wide significance threshold. Studies using the above approaches have identified loci within genes involved in immunity [6,12], vitamin metabolism [10] and complex diseases such as type 2 diabetes [14]. In our study, we aim to further improve statistical power with a novel approach and bring more discoveries from microbiome GWAS.…”