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).

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Results of this large prospective study suggest that Parkinson disease risk is not significantly related to history of hypertension, hypercholesterolemia, or diabetes but may modestly decline with increasing blood cholesterol levels.

Background Predicting susceptibility to multiple sclerosis may have important clinical applications either as part of a diagnostic algorithm or as a tool with which to identify high-risk individuals for prospective studies. Here, we examine the utility of an aggregate measure of risk of multiple sclerosis (MS) based on genetic susceptibility loci. Secondarily, we assess the added effect of environmental risk factors that have been associated with susceptibility for MS. Methods We created a weighted genetic risk score (wGRS) that includes 16 MS susceptibility loci. We tested our model using data from (1) 2215 MS cases and 2189 controls (derivation samples), (2) a validation set of 1340 cases and 1109 controls taken from several MS therapeutic trials (TT samples), and (3) a second validation set of 143 cases and 281 controls from the U.S. Nurses’ Health Studies I and II (NHS) for whom we also have information regarding exposure to smoking and Epstein-Barr Virus (EBV). Findings . Patients with wGRS > 1.25 standard deviations from the mean had a significantly higher odds ratio for MS in all datasets. The area under the curve for a purely genetic model was 0.70 and for a gender + genetic model was 0.74 in the derivation samples (P <0.0001), 0.64 and 0.72 in the TT cohort (P <0.0001). Similarly, consideration of smoking and immune response to EBV enhanced the AUC of 0.64 for the genetic model to 0.68 in the NHS cohort (P =0.02). The wGRS does not appear to be correlated with conversion of a clinically isolated syndrome to MS. Interpretation The current combination of 16 susceptibility alleles into a wGRS modestly predicts MS risk and shows consistent discriminatory ability in independent subject samples and is enhanced by considering non-genetic risk factors.