Abstract
Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10−9 at rs8018720 in SEC23A, and P = 1.9×10−14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene–gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.
Highlights
Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases
In contrast to the previous meta-analysis which involved discovery, in-silico and de-novo genotyping stages, we performed a first stage discovery meta-analysis on a total of up to 79,366 individuals and replicated novel findings in two independent separate in-silico data sets (40,562 individuals collected by European Prospective Investigation into Cancer and Nutrition (EPIC) and 2195 individuals collected by SOCCS)
We identified six susceptibility loci harboring genome-wide significant SNPs, confirming four previously reported loci at GC (P = 4.7×10−343 at rs3755967), NADSYN1/DHCR7 (P = 3.8×10−62 at rs12785878), CYP2R1 (P = 2.1×10−46 at rs10741657), CYP24A1 (P = 8.1×10−23 at rs17216707), and two novel loci at AMDHD1 (P = 1.9×10−14 at rs10745742) and SEC23A (P = 4.7×10−9 at rs8018720) (Table 1; Manhattan plots and QQ-plots for overall samples are presented in Fig. 1, and regional association plots are presented in Supplementary Fig. 2)
Summary
Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. We expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent) This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10−9 at rs8018720 in SEC23A, and P = 1.9×10−14 at rs10745742 in AMDHD1). A larger GWAS conducted by the SUNLIGHT consortium in 16,125 European ancestry individuals, with a replication sample of 17,871, replicated these three loci and discovered one additional locus (CYP24A1)[8] Despite these loci being in or near genes encoding proteins involved in vitamin D synthesis, the associated variants collectively explain only a small fraction of the variance in 25-hydroxyvitamin D concentrations (~5%)[8,11,12]. The genetic instruments identified by our results could be used in future Mendelian Randomization analyses of the association between vitamin D and complex traits
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