title: Exploring the genetic architecture of circulating 25-hydroxyvitamin D.
abstract: 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.
authors.affiliation: Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02215, USA. lindahiraki@mail.harvard.edu
authors.forename: Linda T
authors.initials: LT
authors.lastname: Hiraki
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Major
authors.forename: Constance
authors.initials: C
authors.lastname: Chen
authors.forename: Marilyn C
authors.initials: MC
authors.lastname: Cornelis
authors.forename: David J
authors.initials: DJ
authors.lastname: Hunter
authors.forename: Eric B
authors.initials: EB
authors.lastname: Rimm
authors.forename: Kelly C
authors.initials: KC
authors.lastname: Simon
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Weinstein
authors.forename: Mark P
authors.initials: MP
authors.lastname: Purdue
authors.forename: Kai
authors.initials: K
authors.lastname: Yu
authors.forename: Demetrius
authors.initials: D
authors.lastname: Albanes
authors.forename: Peter
authors.initials: P
authors.lastname: Kraft
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D053493:Cholestanetriol 26-Monooxygenase / Q000235:genetics; D000072467:Cytochrome P450 Family 2; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D020412:Multifactorial Inheritance; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D013250:Steroid Hydroxylases / Q000235:genetics; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000097:blood / Q000235:genetics; D065668:Vitamin D3 24-Hydroxylase
chemical_list: D014807:Vitamin D; C104450:25-hydroxyvitamin D; D013250:Steroid Hydroxylases; D000072467:Cytochrome P450 Family 2; C506833:CYP2R1 protein, human; D053493:Cholestanetriol 26-Monooxygenase; D065668:Vitamin D3 24-Hydroxylase; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019995:7-dehydrocholesterol reductase