Gut fungi are associated with human genetic variation and disease risk

Area of Science:

• Human genetics
• Microbiome research
• Mycology

Background:

• The gut microbiome's role in health and disease is well-established, with a focus on bacteria.
• The influence of human genetics on the gut mycobiome (fungi) remains largely unexplored.
• Understanding host-microbe interactions is crucial for deciphering disease etiology.

Purpose of the Study:

• To conduct the first genome-wide association study (GWAS) to identify human genetic loci influencing gut fungi relative abundance.
• To investigate the association between genetic variations and specific fungal taxa in the human gut.
• To explore potential links between gut mycobiome genetics and chronic diseases like cardiovascular disease.

Main Methods:

• Genome-wide association study (GWAS) to identify fungi-associated variants (FAVs).
• Analysis of genetic associations with 9 distinct fungal taxa.
• Integration of genetic data with gene expression data (fungi-associated expression quantitative trait loci).
• Mendelian two-sample randomization analysis to assess causal relationships.

Main Results:

• Identified 148 FAVs across 7 chromosomes associated with gut fungal abundance.
• Several FAVs were located within protein-coding genes, including PTPRC, ANAPC10, NAV2, and CDH13.
• Discovered a significant association between the gut yeast Kazachstania and genetic variation in CDH13.
• Demonstrated a causal link between Kazachstania abundance and increased cardiovascular disease risk.

Conclusions:

• Human genetics play a significant role in shaping the gut mycobiome composition.
• Genetic variations, particularly in CDH13, are linked to specific gut fungi like Kazachstania.
• These findings reveal a novel connection between host genetics, gut fungi, and cardiovascular disease, expanding the understanding of human-microbe interactions.