Van Syoc Emily P, Davenport Emily R, Bordenstein Seth R
One Health Microbiome Center, Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, Pennsylvania, United States of America.
Department of Biology, The Pennsylvania State University, University Park, Pennsylvania, United States of America.
PLoS Biol. 2025 Sep 2;23(9):e3003339. doi: 10.1371/journal.pbio.3003339. eCollection 2025 Sep.
Human genetic determinants of the gut mycobiome remain uninvestigated despite decades of research highlighting tripartite relationships between gut bacteria, genetic background, and disease. Here, we present the first genome-wide association study on the number and types of human genetic loci influencing gut fungi relative abundance. We detect 148 fungi-associated variants (FAVs) across 7 chromosomes that statistically associate with 9 fungal taxa. Of these FAVs, several occur in the protein-coding genes PTPRC, ANAPC10, NAV2, and CDH13. Additional FAVs link to tissue-specific gene expression as fungi-associated expression quantitative trait loci. Notably, the relative abundance of gut yeast Kazachstania associates with genetic variation in CDH13 encoding T-cadherin, a protein linked to cardiovascular disease. Kazachstania forms a causal relationship with cardiovascular disease risk in a mendelian two-sample randomization analysis. These findings establish previously unrecognized connections between human genetics, gut fungi, and chronic disease, broadening the paradigm of human-microbe interactions in the gut to the mycobiome.
尽管数十年来的研究都强调了肠道细菌、遗传背景和疾病之间的三方关系，但肠道真菌群的人类遗传决定因素仍未得到研究。在此，我们首次进行了全基因组关联研究，以探究影响肠道真菌相对丰度的人类遗传位点的数量和类型。我们在7条染色体上检测到148个与真菌相关的变异（FAV），这些变异与9个真菌分类群存在统计学关联。在这些FAV中，有几个出现在蛋白质编码基因PTPRC、ANAPC10、NAV2和CDH13中。其他FAV则作为与真菌相关的表达数量性状位点与组织特异性基因表达相关联。值得注意的是，肠道酵母Kazachstania的相对丰度与编码T-钙黏蛋白的CDH13基因的遗传变异相关，T-钙黏蛋白是一种与心血管疾病相关的蛋白质。在孟德尔双样本随机化分析中，Kazachstania与心血管疾病风险形成了因果关系。这些发现建立了人类遗传学、肠道真菌和慢性疾病之间以前未被认识到的联系，将肠道中人类与微生物相互作用的范式扩展到真菌群。
