rs7940244 — NADSYN1 Near DHCR7

Intronic NADSYN1 variant in the DHCR7/NADSYN1 vitamin D locus; T allele tags the lower-vitamin-D haplotype, reducing 7-dehydrocholesterol availability for skin vitamin D3 synthesis

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NADSYN1 rs7940244 — A Vitamin D Locus Hidden in a Neighboring Gene

Every cell in your skin can convert sunlight into vitamin D — but only if it has enough [7-dehydrocholesterol (7-DHC) | A cholesterol precursor concentrated in the stratum basale and stratum spinosum of the epidermis; UVB radiation (290–315 nm) breaks its B-ring open to form previtamin D3] to work with. The problem is that 7-DHC is a shared substrate: the same molecule that becomes vitamin D3 in sunlight can also be converted to cholesterol by the enzyme DHCR7 (7-dehydrocholesterol reductase). These two pathways compete on a molecular level, and the genetic variants near DHCR7 tip the balance.

rs7940244 sits in an intron of NADSYN1 (NAD synthetase 1) on chromosome 11, about 61 kilobases downstream from DHCR7. Despite its address in a different gene, this variant is a strong proxy for the canonical DHCR7 vitamin D locus — it travels on the same haplotype block as rs12785878, the primary GWAS hit for serum 25-hydroxyvitamin D levels at this locus. The T allele of rs7940244 co-segregates with the allele of rs12785878 associated with lower circulating vitamin D, almost certainly because both track a regulatory change that modulates DHCR7 expression or activity.

The Mechanism

DHCR7 catalyzes the [final step in the Kandutsch-Russell cholesterol synthesis pathway | One of two cellular routes to cholesterol; DHCR7 uses NADPH to reduce the C7-8 double bond in 7-DHC, converting it irreversibly to cholesterol on the smooth endoplasmic reticulum membrane] by reducing 7-DHC to cholesterol. Every molecule of 7-DHC that DHCR7 converts to cholesterol is a molecule that cannot become vitamin D3. Variants in this region that increase DHCR7 activity or expression therefore lower the skin's capacity for UV-driven vitamin D synthesis, even under identical sun exposure.

The rs7940244 T allele is not itself a coding change — it does not alter any amino acid in NADSYN1. It is a tag SNP for a nearby regulatory haplotype that influences DHCR7 transcription. The precise functional mechanism remains to be defined by eQTL or reporter studies, but the epidemiological signal is clear and has been replicated across populations totaling hundreds of thousands of individuals.

The DHCR7 protein is also subject to a [cholesterol-mediated feedback loop | When cellular cholesterol rises, cholesterol directly accelerates DHCR7 proteasomal degradation, which reduces its activity and allows 7-DHC to accumulate — favoring vitamin D synthesis] that normally balances vitamin D and cholesterol production. Variants that constitutively elevate DHCR7 activity blunt this feedback response.

The Evidence

The DHCR7/NADSYN1 locus is one of the most robustly replicated genetic determinants of circulating vitamin D. The 2010 Lancet GWAS11 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 this locus at P = 2.1×10⁻²⁷. In the Framingham Heart Study subcohort, mean 25(OH)D differed by approximately 8 nmol/L between the low-risk and high-risk homozygous genotypes. Each additional risk allele increased odds of vitamin D insufficiency (below 75 nmol/L) by approximately 21%.

A concurrent GWAS by Ahn et al.22 GWAS by Ahn et al.
Ahn J et al. Genome-wide association study of circulating vitamin D levels. Hum Mol Genet, 2010 independently confirmed the locus at P = 3.4×10⁻⁹ in 6,722 individuals. More recently, a UK Biobank GWAS in 401,460 participants33 UK Biobank GWAS in 401,460 participants
Manousaki D et al. Am J Hum Genet, 2020 identified 69 vitamin D loci including DHCR7, and a parallel study of 417,580 Europeans44 study of 417,580 Europeans
Revez JA et al. Nat Commun, 2020 identified 143 loci with DHCR7 remaining one of the strongest signals.

The rs7940244 T allele is notably rare in Europeans (~22%) but common in African (~48%) and South Asian populations (~67%), a pattern consistent with a positive selection signal in ancient Europeans55 positive selection signal in ancient Europeans
Mathieson I et al. Genome-wide patterns of selection in 230 ancient Eurasians. Nature, 2015 and with the evolutionary hypothesis that, as humans migrated north from equatorial Africa into low-UV environments, variants that preserved 7-DHC for vitamin D synthesis (rather than diverting it to cholesterol) conferred a survival advantage against rickets and immune dysfunction.

Practical Implications

The per-allele effect at the DHCR7/NADSYN1 locus on vitamin D levels is modest — approximately 2–4 nmol/L (about 1 ng/mL) per risk allele — but the biological message is actionable: T allele carriers have a genetic tendency to produce less vitamin D3 from a given amount of sun exposure. This tendency compounds with the environmental risk factors that dominate overall vitamin D status: high latitude, winter season, indoor lifestyle, darker skin, and obesity. For T allele carriers, monitoring vitamin D levels and adjusting supplementation accordingly is more important than for those without this variant.

Critically, this variant affects only the skin synthesis pathway. It does not impair absorption of dietary or supplemental vitamin D. Supplementing with cholecalciferol (D3) or spending more time in direct midday sun are both effective countermeasures.

Interactions

rs7940244 is in strong LD with rs12785878 (r² = 0.703, D' = 0.987 in Europeans), meaning it captures much of the same biological signal. If both rs7940244 and rs12785878 are present in a genome report, they should not be interpreted as independent effects — they reflect the same underlying haplotype.

The three other major vitamin D pathway loci interact with this locus 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. A combined genetic risk score across these four loci increases odds of insufficiency by up to 2.47-fold compared to the most favorable genotype.

Nutrient Interactions

vitamin D impaired_conversion

Genotype Interpretations

What each possible genotype means for this variant.

CC Optimal Vitamin D Synthesis Normal

Favorable DHCR7 haplotype — normal vitamin D synthesis capacity

The CC genotype at rs7940244 places you on the favorable end of the DHCR7/NADSYN1 vitamin D haplotype. This locus has been genome-wide significant in multiple GWAS studies totaling over 400,000 individuals, with each risk (T) allele reducing mean serum 25(OH)D by approximately 2–4 nmol/L. As a CC carrier, you do not carry any copies of the lower-vitamin-D allele at this locus.

Your actual vitamin D status still depends predominantly on sun exposure, latitude, season, skin pigmentation, dietary intake, and body composition. A serum 25(OH)D test remains the most reliable way to assess your individual status, regardless of genotype.

CT Mildly Reduced Synthesis Intermediate

One copy of the lower-vitamin-D allele — modest reduction in skin vitamin D synthesis

The CT genotype represents one copy of the DHCR7/NADSYN1 risk haplotype, with an intermediate effect between CC and TT. The additive effect at this locus means one copy has roughly half the impact of two copies. For most CT carriers, adequate sun exposure and standard dietary intake will maintain sufficient vitamin D levels.

However, this modest genetic disadvantage becomes more meaningful when combined with other risk factors: living at latitudes above 40°N, spending most of the day indoors, having darker skin, or carrying additional risk alleles at other vitamin D pathway genes (CYP2R1, GC, CYP24A1). Monitoring is advisable if any of these apply.

TT Reduced Vitamin D Synthesis Reduced

Two copies of the lower-vitamin-D allele — genetically reduced skin vitamin D synthesis

The TT genotype carries two copies of the risk haplotype at the DHCR7/NADSYN1 locus — the strongest genetic effect at this variant. In the landmark 2010 Lancet GWAS by Wang et al., homozygous risk carriers showed mean 25(OH)D levels approximately 8 nmol/L lower than the most favorable homozygous genotype, sufficient to shift many individuals from adequate to insufficient vitamin D status, especially during winter.

This effect is additive: TT carriers have roughly twice the genetically determined reduction in vitamin D synthesis as CT carriers. When combined with other major vitamin D pathway variants (CYP2R1, GC, CYP24A1 loci), the cumulative genetic risk can increase odds of vitamin D insufficiency by up to 2.47-fold.

This variant affects only skin synthesis. Dietary vitamin D (from fatty fish, egg yolks, fortified foods) and supplements are fully effective regardless of DHCR7 genotype, since they bypass the skin pathway entirely.