rs12785878 — DHCR7 Near gene T>G

DHCR7 and the Cholesterol-Vitamin D Switch

Your skin makes vitamin D through an elegant two-step process: ultraviolet B light strikes 7-dehydrocholesterol (7-DHC)¹¹ 7-dehydrocholesterol (7-DHC)
A cholesterol precursor molecule concentrated in the outer layers of your skin, particularly the stratum basale and stratum spinosum in the outer skin layers, breaking open one of its carbon rings to form previtamin D3, which then spontaneously rearranges into vitamin D3 (cholecalciferol). But there is a catch: the same 7-DHC molecule is also the substrate for DHCR7 (7-dehydrocholesterol reductase), the enzyme that converts it into cholesterol. These two pathways compete for the same precursor, making DHCR7 a metabolic switch that determines how much of your skin's 7-DHC goes toward vitamin D versus cholesterol.

The variant rs12785878 sits near the DHCR7 gene on chromosome 11. While it does not change the protein's amino acid sequence, it is associated with altered DHCR7 expression or activity. The G allele is linked to lower circulating 25-hydroxyvitamin D²² 25-hydroxyvitamin D
25(OH)D, also called calcidiol, is the main circulating form of vitamin D measured in blood tests. It reflects your overall vitamin D status from both sun exposure and diet levels, likely because higher DHCR7 activity channels more 7-DHC toward cholesterol and away from the vitamin D synthesis pathway.

The Mechanism

DHCR7 catalyzes the final step in the Kandutsch-Russell cholesterol synthesis pathway³³ final step in the Kandutsch-Russell cholesterol synthesis pathway
This is one of two routes cells use to make cholesterol. DHCR7 reduces the C7-8 double bond in 7-DHC using NADPH as an electron donor, converting 7-DHC to cholesterol on the smooth endoplasmic reticulum. In a feedback loop, cholesterol itself accelerates the proteasomal degradation of DHCR7 protein, which in turn increases 7-DHC accumulation and favors vitamin D production. When genetic variants increase baseline DHCR7 activity or expression, less 7-DHC remains available for UV-driven vitamin D synthesis in the skin.

The rs12785878 variant is technically located in an intron of the neighboring NADSYN1 gene, but the associated signal maps to the DHCR7 regulatory region. Multiple SNPs in tight linkage disequilibrium⁴⁴ linkage disequilibrium
LD: a measure of how strongly alleles at nearby positions are inherited together. High LD means the alleles travel as a block through generations span this locus, and the functional effect likely involves regulatory changes that modulate DHCR7 transcription.

The Evidence

The landmark 2010 Lancet GWAS⁵⁵ landmark 2010 Lancet GWAS
Wang TJ et al. Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet, 2010 in 33,996 Europeans identified rs12785878 as one of three loci reaching genome-wide significance for association with 25(OH)D concentrations (P = 2.1 x 10^-27). In the Framingham Heart Study subcohort, mean 25(OH)D differed by about 8 nmol/L between TT homozygotes (79.7 nmol/L) and GG homozygotes (71.7 nmol/L). Each copy of the G allele increased the odds of vitamin D insufficiency (below 75 nmol/L) by about 21% (OR 1.21, 95% CI 1.14-1.29).

A concurrent GWAS by Ahn and colleagues⁶⁶ GWAS by Ahn and colleagues
Ahn J et al. Genome-wide association study of circulating vitamin D levels. Hum Mol Genet, 2010 independently confirmed the DHCR7/NADSYN1 locus at P = 3.4 x 10^-9 in 6,722 individuals, finding this region accounted for approximately 1.2% of the variance in circulating vitamin D levels.

These findings have been massively replicated. A UK Biobank GWAS⁷⁷ UK Biobank GWAS
Manousaki D et al. Genome-wide association study for vitamin D levels reveals 69 independent loci. Am J Hum Genet, 2020 in 401,460 participants confirmed DHCR7 among 69 loci for vitamin D, and a parallel study of 417,580 Europeans⁸⁸ study of 417,580 Europeans
Revez JA et al. Genome-wide association study identifies 143 loci associated with 25 hydroxyvitamin D concentration. Nat Commun, 2020 identified 143 loci, with DHCR7 remaining one of the strongest signals.

Beyond vitamin D levels, the G allele has been associated with increased risk of multiple sclerosis in a genome-wide study⁹⁹ genome-wide study
Australia and New Zealand Multiple Sclerosis Genetics Consortium. Genes Immun, 2011 and with early-onset Alzheimer's disease in a Chinese case-control study¹⁰¹⁰ Chinese case-control study
Ma M et al. Front Genet, 2021 (OR 1.54, 95% CI 1.18-2.02), both of which may be mediated through vitamin D's immunomodulatory and neuroprotective roles.

Practical Implications

The per-allele effect of rs12785878 on vitamin D levels is modest (roughly 2-4 nmol/L, or about 1 ng/mL per G allele), but it compounds with other risk factors: limited sun exposure, darker skin pigmentation, higher latitude, indoor lifestyle, and winter season. Individuals with the GG genotype who also have other vitamin D pathway variants (such as reduced CYP2R1 hydroxylation or altered GC/DBP transport) may be especially prone to insufficiency.

The practical message is straightforward: if you carry one or two copies of the G allele, you have a genetic tendency toward lower vitamin D production from sunlight. Monitoring your 25(OH)D levels and supplementing as needed becomes more important, particularly if you live at higher latitudes or have limited sun exposure.

Evolutionary Context

The T allele (associated with higher vitamin D) shows a striking latitude gradient: it reaches 74% frequency in European populations but only 18% in African populations. A 2013 evolutionary study¹¹¹¹ 2013 evolutionary study
Kuan V et al. DHCR7 mutations linked to higher vitamin D status allowed early human migration to northern latitudes. BMC Evol Biol, 2013 found evidence of positive selection for DHCR7 haplotypes associated with higher vitamin D at northern latitudes. As humans migrated away from equatorial Africa to regions with less intense UV radiation, variants that preserved more 7-DHC for vitamin D synthesis (rather than shunting it to cholesterol) provided a survival advantage against rickets, immune dysfunction, and reduced fertility.

Interactions

The three other major vitamin D pathway loci interact with rs12785878 in determining overall vitamin D status. CYP2R1 (rs10741657) encodes the liver 25-hydroxylase that converts vitamin D3 to 25(OH)D. GC (rs2282679) encodes the vitamin D binding protein that transports 25(OH)D in the blood. CYP24A1 (rs6013897) encodes the enzyme that degrades active vitamin D. Wang et al. found that individuals in the highest quartile of a combined genetic risk score across these loci had 2.47 times the odds of vitamin D insufficiency compared to the lowest quartile. These multi-gene interactions may warrant compound implications when a user carries risk alleles at multiple vitamin D pathway loci.