rs117576073 (CYP2R1): Vitamin D Metabolism Variant

Key takeaways

• rs117576073 sits in CYP2R1 (cytochrome P450 family 2 subfamily R member 1), a gene encoding an enzyme that converts vitamin D into 25-hydroxyvitamin D (25OHD), the main form measured in blood tests.
• This gene's region is one of the most consistently replicated genetic loci for circulating vitamin D levels, identified across independent GWAS studies of up to 417,580 participants.
• Mendelian randomization finds no robust evidence that higher 25OHD levels cause changes in BMI or psychiatric health; many health conditions appear to causally lower vitamin D rather than the reverse.
• One cross-trait GWAS analysis linked genetically predicted higher vitamin D to roughly 6% lower COVID-19 infection risk (OR = 0.94), though this is preliminary single-study evidence.
• The alternative allele of rs117576073 is associated with increased CYP2R1 expression specifically in cerebellar brain tissue, according to GTEx eQTL data.

What the research says CYP2R1 encodes an enzyme that performs a key hydroxylation step in vitamin D metabolism, converting dietary and skin-synthesized vitamin D into 25OHD, the form assayed to estimate vitamin D status; it is classified as part of the canonical vitamin D metabolic pathway. A GWAS in 417,580 Europeans identified 143 independent loci for 25OHD including this locus, with common SNPs explaining approximately 7.5% (SE 1.9%) of 25OHD variance, and Mendelian randomization in the same study found no robust causal evidence that 25OHD concentration drives BMI, psychiatric disorders, or other candidate phenotypes, while many phenotypes showed causal effects on 25OHD PMID 33293526. A separate large-scale GWAS in 401,460 UK Biobank participants estimated 25OHD SNP heritability at 16.1%, identified 69 distinct loci including this gene among canonical pathway genes, and found enrichment in hepatic and lipid metabolism pathways with expression enriched in liver, skin, and gastrointestinal tissues PMID 32891193.

Reported associations

• 25-hydroxyvitamin D concentration: A GWAS in 417,580 Europeans identified CYP2R1 among 143 independent 25OHD loci; common SNPs at this and nearby regions collectively explain approximately 7.5% (SE 1.9%) of 25OHD variance PMID 33293526
• 25-hydroxyvitamin D concentration: A GWAS in 401,460 UK Biobank participants identified this locus among 69 distinct 25OHD associations (138 conditionally independent SNPs detected at p < 6.6e-9), with SNP heritability estimated at 16.1% PMID 32891193
• Blood biomarker levels: A UK Biobank GWAS of 35 blood and urine biomarkers (n = 363,228) identified 1,857 associated loci including variants in vitamin D metabolism pathways, with fine-mapped associations and polygenic risk scores developed for each biomarker PMID 33558757
• COVID-19 infection susceptibility: Cross-trait GWAS and Mendelian randomization found a significant genetic correlation between vitamin D and COVID-19 (r = -0.143, p = 0.011); genetically predicted higher 25OHD was associated with approximately 6% lower COVID-19 infection risk (OR = 0.94, 95% CI: 0.89-0.99) per 0.76 nmol/L increase in 25OHD PMID 36807974

Evidence quality The CYP2R1 locus has well-established, replicated evidence as a determinant of circulating 25OHD, confirmed across independent cohorts totaling over 780,000 participants combined PMID 33293526 PMID 32891193 PMID 33558757. The specific variant rs117576073 is not individually named in the provided studies; the associations described here reflect the broader locus. A notable and potentially counterintuitive finding from Revez et al. (n = 417,580) is that while CYP2R1-region variants robustly associate with 25OHD levels, Mendelian randomization found no robust evidence that 25OHD itself causally drives BMI, psychiatric disorders, or other tested phenotypes; the reverse direction, where phenotypes have causal effects on 25OHD, was more strongly supported PMID 33293526. The COVID-19 finding (OR = 0.94, p = 0.019) is from a single cross-trait analysis using a generalized Mendelian randomization framework and is considered preliminary pending independent replication PMID 36807974.

Tissue-specific expression effects

• CYP2R1: The alternative allele of rs117576073 is associated with increased expression of the gene in two cerebellar brain regions: the cerebellum and the cerebellar hemisphere; both effects are significant at FDR < 0.05 in GTEx v11 data (953 donors). This is a cis-eQTL (a variant that regulates expression of a nearby gene) effect. The clinical relevance of increased CYP2R1 expression specifically in cerebellar tissue is not established in the studies reviewed here GTEx Portal

Lifestyle considerations

• Vitamin D supplementation (supplements, mixed, low): CYP2R1 encodes the enzyme responsible for the first hydroxylation step in vitamin D processing, meaning variants here may affect how efficiently dietary or supplemental vitamin D is converted to its circulating form; however, the reviewed studies establish associations at the population level only and do not provide genotype-specific supplementation guidance for rs117576073.