Genome-wide association study of circulating vitamin D levels

Abstract

The primary circulating form of vitamin D, 25-hydroxy-vitamin D [25(OH)D], is associated with multiple medical outcomes, including rickets, osteoporosis, multiple sclerosis and cancer. In a genome-wide association study (GWAS) of 4501 persons of European ancestry drawn from five cohorts, we identified single-nucleotide polymorphisms (SNPs) in the gene encoding group-specific component (vitamin D binding) protein, GC, on chromosome 4q12-13 that were associated with 25(OH)D concentrations: rs2282679 (P = 2.0 × 10−30), in linkage disequilibrium (LD) with rs7041, a non-synonymous SNP (D432E; P = 4.1 × 10−22) and rs1155563 (P = 3.8 × 10−25). Suggestive signals for association with 25(OH)D were also observed for SNPs in or near three other genes involved in vitamin D synthesis or activation: rs3829251 on chromosome 11q13.4 in NADSYN1 [encoding nicotinamide adenine dinucleotide (NAD) synthetase; P = 8.8 × 10−7], which was in high LD with rs1790349, located in DHCR7, the gene encoding 7-dehydrocholesterol reductase that synthesizes cholesterol from 7-dehydrocholesterol; rs6599638 in the region harboring the open-reading frame 88 (C10orf88) on chromosome 10q26.13 in the vicinity of ACADSB (acyl-Coenzyme A dehydrogenase), involved in cholesterol and vitamin D synthesis (P = 3.3 × 10−7); and rs2060793 on chromosome 11p15.2 in CYP2R1 (cytochrome P450, family 2, subfamily R, polypeptide 1, encoding a key C-25 hydroxylase that converts vitamin D3 to an active vitamin D receptor ligand; P = 1.4 × 10−5). We genotyped SNPs in these four regions in 2221 additional samples and confirmed strong genome-wide significant associations with 25(OH)D through meta-analysis with the GWAS data for GC (P = 1.8 × 10−49), NADSYN1/DHCR7 (P = 3.4 × 10−9) and CYP2R1 (P = 2.9 × 10−17), but not C10orf88 (P = 2.4 × 10−5).

Association of vitamin D-related gene polymorphisms with manifestation of vitamin D deficiency in children

“…Moreover, the association of rs3829251 with reduced 25(OH)D levels was also found in a Chinese cohort [14]. rs705117 in GC is 268 bp away from rs2282679, which is associated with reduced 25(OH)D levels in both Caucasians and Chinese [11,12,14]. We believe that polymorphisms in these genes are also associated with low 25(OH)D levels in the Japanese population.…”

“…D levels in a GWAS [11]. Moreover, the association of rs3829251 with reduced 25(OH)D levels was also found in a Chinese cohort [14].…”

“…We selected polymorphisms that have been reported to be associated with serum 25(OH)D levels in either GWAS or candidate gene studies [8,9,11,12,[15][16][17][18][19][20]. Well-known VDR polymorphisms reported to be associated with bone mineral density and several vitamin D-related diseases were also included [21][22][23].…”

Assessing the causal association between 25‐hydroxyvitamin D and the risk of oral and oropharyngeal cancer using Mendelian randomization

“…Common genetic variants have been identified in Genome Wide Association Studies (GWAS)21, 22 of 25OHD, only variants that passed a genome wide association threshold ( p  < 5 × 10 −8 ) and had been replicated were selected. These genetic proxies or instruments are located in or near four 25OHD related genes: Group‐specific component ( GC ), cytochrome P450 family 2, subfamily R, polypeptide 1 ( CYP2R1 ), 7‐dehydrocholesterol reductase ( DHCR7 ) and cytochrome P450, family 24, polypeptide 1 ( CYP24A1 ).…”

ANKRD55 and DHCR7 are novel multiple sclerosis risk loci

“…30,31 Notch signaling is involved in immune responses and tissue repair mechanisms pertinent to MS. 32 The second significantly associated gene arising from this study, albeit with much smaller genetic effect, DHCR7, was recently discovered in two GWAS on vitamin D insufficiency. 12,13 Rs12785878 is located in the second intron of the NADSYN1 gene, Figure 1). 14 Several studies have analyzed vitamin D metabolic pathway genes as determinants of risk for MS, generally with negative outcomes.…”