Tonnele Helene, Chen Denghui, Morillo Felipe, Garcia-Calleja Jorge, Chitre Apurva S, Johnson Benjamin B, Sanches Thiago Missfeldt, Bonder Marc Jan, Gonzalez Antonio, Kosciolek Tomasz, George Anthony M, Han Wenyan, Holl Katie, Horvath Aidan, Ishiwari Keita, King Christopher P, Lamparelli Alexander C, Martin Connor D, Martinez Angel Garcia, Netzley Alesa H, Tripi Jordan A, Wang Tengfei, Bosch Elena, Doris Peter A, Stegle Oliver, Chen Hao, Flagel Shelly B, Meyer Paul J, Richards Jerry B, Robinson Terry E, Woods Leah C Solberg, Polesskaya Oksana, Knight Rob, Palmer Abraham A, Baud Amelie
Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Spain.
Universitat Pompeu Fabra, Barcelona, Spain.
bioRxiv. 2025 Mar 27:2025.03.20.644349. doi: 10.1101/2025.03.20.644349.
The intestinal microbiome influences health and disease. Its composition is affected by host genetics and environmental exposures. Understanding host genetic effects is critical but challenging in humans, due to the difficulty of detecting, mapping and interpreting them. To address this, we analysed host genetic effects in four cohorts of outbred laboratory rats exposed to distinct but controlled environments. We found that polygenic host genetic effects were consistent across environments. We identified three replicated microbiome-associated loci. One involved a sialyltransferase gene and and we found a similar association, between and , in a human cohort. Given 's known immunity-potentiating functions, this suggests 's effects on IgA nephropathy and COVID-19 breakthrough infections may be mediated by . Moreover, we found evidence of indirect genetic effects on microbiome phenotypes, which substantially increased their total genetic variance. Finally, we identified a novel mechanism whereby indirect genetic effects can contribute to "missing heritability".
肠道微生物群影响健康和疾病。其组成受宿主基因和环境暴露的影响。了解宿主基因效应至关重要，但在人类中具有挑战性，因为难以检测、定位和解释这些效应。为了解决这个问题，我们分析了暴露于不同但可控环境的四个远交系实验大鼠群体中的宿主基因效应。我们发现多基因宿主基因效应在不同环境中是一致的。我们鉴定出三个重复的微生物群相关基因座。其中一个涉及唾液酸转移酶基因，并且我们在一个人类群体中发现了类似的关联。鉴于其已知的免疫增强功能，这表明其对IgA肾病和COVID-19突破性感染的影响可能由介导。此外，我们发现了对微生物群表型的间接基因效应的证据，这大大增加了它们的总遗传方差。最后，我们确定了一种新机制，通过该机制间接基因效应可导致“遗传力缺失”。
