Exploring the Genetic Architecture of Circulating 25-Hydroxyvitamin D

Linda T. Hiraki*, Jacqueline M. Major, Constance Chen, Marilyn C. Cornelis, David J. Hunter, Eric B. Rimm, Kelly C. Simon, Stephanie J. Weinstein, Mark P. Purdue, Kai Yu, Demetrius Albanes, Peter Kraft

*Corresponding author for this work

Research output: Contribution to journalArticle

28 Scopus citations


The 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 0-22%). The absence of a significant polygenic effect in this relatively large sample suggests an oligogenetic architecture for 25(OH)D.

Original languageEnglish (US)
Pages (from-to)92-98
Number of pages7
JournalGenetic Epidemiology
Issue number1
StatePublished - Jan 1 2013


  • Genome-wide association
  • Heritability
  • Polygenic score
  • Vitamin D

ASJC Scopus subject areas

  • Epidemiology
  • Genetics(clinical)

Fingerprint Dive into the research topics of 'Exploring the Genetic Architecture of Circulating 25-Hydroxyvitamin D'. Together they form a unique fingerprint.

  • Cite this

    Hiraki, L. T., Major, J. M., Chen, C., Cornelis, M. C., Hunter, D. J., Rimm, E. B., Simon, K. C., Weinstein, S. J., Purdue, M. P., Yu, K., Albanes, D., & Kraft, P. (2013). Exploring the Genetic Architecture of Circulating 25-Hydroxyvitamin D. Genetic Epidemiology, 37(1), 92-98. https://doi.org/10.1002/gepi.21694