Genetic influences on circulating retinol and its relationship to human health.

Nature communications 2024 Feb 19

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Retinol is a fat-soluble vitamin that plays an essential role in many biological processes throughout the human lifespan. Here, we perform the largest genome-wide association study (GWAS) of retinol to date in up to 22,274 participants. We identify eight common variant loci associated with retinol, as well as a rare-variant signal. An integrative gene prioritisation pipeline supports novel retinol-associated genes outside of the main retinol transport complex (RBP4:TTR) related to lipid biology, energy homoeostasis, and endocrine signalling. Genetic proxies of circulating retinol were then used to estimate causal relationships with almost 20,000 clinical phenotypes via a phenome-wide Mendelian randomisation study (MR-pheWAS). The MR-pheWAS suggests that retinol may exert causal effects on inflammation, adiposity, ocular measures, the microbiome, and MRI-derived brain phenotypes, amongst several others. Conversely, circulating retinol may be causally influenced by factors including lipids and serum creatinine. Finally, we demonstrate how a retinol polygenic score could identify individuals more likely to fall outside of the normative range of circulating retinol for a given age. In summary, this study provides a comprehensive evaluation of the genetics of circulating retinol, as well as revealing traits which should be prioritised for further investigation with respect to retinol related therapies or nutritional intervention. © 2024. The Author(s).

Citation

William R Reay, Dylan J Kiltschewskij, Maria A Di Biase, Zachary F Gerring, Kousik Kundu, Praveen Surendran, Laura A Greco, Erin D Clarke, Clare E Collins, Alison M Mondul, Demetrius Albanes, Murray J Cairns. Genetic influences on circulating retinol and its relationship to human health. Nature communications. 2024 Feb 19;15(1):1490