Genetic influences on circulating retinol and its relationship to human health

Retinol is a fat-soluble vitamin that plays an essential role in many biological processes throughout the human lifespan. Previous work has characterised genetic influences on circulating retinol; however, small sample sizes have limited our ability to fully appreciate the genetic architecture of this trait. In this study, we performed the largest genome-wide association study (GWAS) of retinol to date in up to 22,274 participants. We identified eight common variant loci associated with retinol, as well as a rare-variant signal. An integrative gene prioritisation pipeline supported novel retinol-associated genes outside of the main retinol transport complex (RBP4:TTR) related to lipid biology, energy homeostasis, 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 suggested 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 renal function. Finally, we demonstrated how a retinol polygenic score could identify individuals who are 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 clinical investigation with respect to retinol related therapies or nutritional intervention.