Genetic influences on circulating retinol and its relationship to human health

William R. Reay (), Dylan J. Kiltschewskij, Maria A. Biase, Zachary F. Gerring, Kousik Kundu, Praveen Surendran, Laura A. Greco, Erin D. Clarke, Clare E. Collins, Alison M. Mondul, Demetrius Albanes and Murray J. Cairns ()
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William R. Reay: The University of Newcastle
Dylan J. Kiltschewskij: The University of Newcastle
Maria A. Biase: The University of Melbourne
Zachary F. Gerring: QIMR Berghofer Medical Research Institute
Kousik Kundu: Wellcome Genome Campus
Praveen Surendran: University of Cambridge
Laura A. Greco: The University of Newcastle
Erin D. Clarke: The University of Newcastle
Clare E. Collins: The University of Newcastle
Alison M. Mondul: University of Michigan School of Public Health
Demetrius Albanes: NIH, Department of Health and Human Services
Murray J. Cairns: The University of Newcastle

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-45779-x

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