Large-scale association analyses identify host factors influencing human gut microbiome composition

Area of Science:

• Human Genetics
• Microbiome Research
• Systems Biology

Background:

• The gut microbiome's composition is influenced by numerous factors, including host genetics.
• Understanding these genetic influences is crucial for deciphering host-microbe interactions and their health implications.

Purpose of the Study:

• To investigate the impact of host genetic variation on gut microbiome composition using a large-scale, multi-cohort dataset.
• To identify specific genetic loci associated with microbial taxa and explore their functional relevance.

Main Methods:

• Genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals across 24 cohorts were analyzed.
• Genome-wide association studies (GWAS) were performed to identify host genetic loci associated with microbial taxa.
• Phenome-wide association studies (PheWAS) and Mendelian randomization (MR) were employed to explore phenotypic associations and causal relationships.

Main Results:

• 31 loci were identified with genome-wide significant associations (P < 5x10^-8) with microbial taxa.
• The lactase (LCT) gene locus showed a highly significant association (P = 1.28x10^-20) and an age-dependent effect on Bifidobacterium abundance.
• Enrichment analysis revealed associations with heritable taxa and genes expressed in the intestine and brain, suggesting functional links.

Conclusions:

• Host genetics play a significant role in shaping the gut microbiome, with identified loci providing insights into host-microbe interactions.
• The gut microbiome may have causal roles in diseases such as ulcerative colitis and rheumatoid arthritis, warranting further investigation.
• These findings highlight the complex interplay between host genetics, the microbiome, and human health.