Hiraki, Linda T.Major, Jacqueline M.Chen, ConstanceCornelis, Marilyn C.Hunter, David J.Rimm, Eric Bruce::0ab2926c8242f35e5a982e3cf59f4987::600Simon, Kelly C.Weinstein, Stephanie J.Purdue, Mark P.Yu, KaiAlbanes, DemetriusKraft, Peter2019-08-262013Hiraki, Linda T., Jacqueline M. Major, Constance Chen, Marilyn C. Cornelis, David J. Hunter, Eric B. Rimm, Kelly C. Simon, et al. 2012. “Exploring the Genetic Architecture of Circulating 25-Hydroxyvitamin D.” Genetic Epidemiology 37 (1): 92–98. https://doi.org/10.1002/gepi.21694.0741-03951098-2272http://nrs.harvard.edu/urn-3:HUL.InstRepos:41247262The primary circulating form of vitamin D is 25-hydroxy vitamin D (25(OH)D), a modifiable trait linked with a growing number of chronic diseases. In addition to environmental determinants of 25(OH)D, including dietary sources and skin ultraviolet B (UVB) exposure, twin- and family-based studies suggest that genetics contribute substantially to vitamin D variability with heritability estimates ranging from 43% to 80%. Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) located in four gene regions associated with 25(OH)D. These SNPs collectively explain only a fraction of the heritability in 25(OH)D estimated by twin- and family-based studies. Using 25(OH)D concentrations and GWAS data on 5,575 subjects drawn from five cohorts, we hypothesized that genome-wide data, in the form of (1) a polygenic score comprised of hundreds or thousands of SNPs that do not individually reach GWAS significance, or (2) a linear mixed model for genome-wide complex trait analysis, would explain variance in measured circulating 25(OH)D beyond that explained by known genome-wide significant 25(OH)D-associated SNPs. GWAS identified SNPs explained 5.2% of the variation in circulating 25(OH)D in these samples and there was little evidence additional markers significantly improved predictive ability. On average, a polygenic score comprised of GWAS-identified SNPs explained a larger proportion of variation in circulating 25(OH)D than scores comprised of thousands of SNPs that were on average, nonsignificant. Employing a linear mixed model for genome-wide complex trait analysis explained little additional variability (range 022%). The absence of a significant polygenic effect in this relatively large sample suggests an oligogenetic architecture for 25(OH)D.en-USJournal Article2019-08-2610.1002/gepi.21694