rs10745742 — AMDHD1

AMDHD1 — A Histidine-Catabolism Gene That Shapes Vitamin D Status

Most genetic variants that affect your circulating vitamin D levels do so through obvious routes: altering UV-driven skin synthesis (DHCR7), speeding or slowing the liver's 25-hydroxylation step (CYP2R1), changing how efficiently vitamin D binds its transport protein in the blood (GC), or controlling how quickly active vitamin D is broken down (CYP24A1). The variant rs10745742 in AMDHD1¹¹ AMDHD1
Amidohydrolase Domain Containing 1, also known as HUTI — a 426-amino acid enzyme in the histidine degradation pathway is different. It represents a newly discovered connection between amino acid catabolism and vitamin D homeostasis — a pathway that was not previously recognized as relevant to vitamin D status.

The Mechanism

AMDHD1 encodes an imidazolonepropionase — the third enzyme in the histidine catabolism pathway²² histidine catabolism pathway
The five-step enzymatic cascade that degrades the amino acid histidine into glutamate via urocanate, imidazolone propionate, and formiminoglutamate. Specifically, AMDHD1 catalyzes the hydrolysis of 4-imidazolone-5-propionate to produce N-formimino-L-glutamate (FIGLU)³³ N-formimino-L-glutamate (FIGLU)
FIGLU is the penultimate metabolite in histidine catabolism. It donates a formimino group to tetrahydrofolate (THF), generating glutamate and 5-formimino-THF — a one-carbon THF intermediate that feeds into the folate/one-carbon pool. This step directly links histidine breakdown to the folate one-carbon pool⁴⁴ folate one-carbon pool
The biochemical network centered on tetrahydrofolate that shuttles single-carbon units for methylation reactions, nucleotide synthesis, and amino acid interconversion. One-carbon metabolism supports vitamin D hydroxylation steps through NADPH regeneration and methylation of regulatory proteins, a central hub of cellular metabolism.

Reduced AMDHD1 activity — the likely consequence of the C allele at rs10745742 — may impair histidine-to-FIGLU conversion, reducing the flow of one-carbon units into the folate pool. Because vitamin D hydroxylation enzymes (CYP2R1, CYP27B1, CYP24A1) depend on cellular metabolism for cofactor availability, perturbations in this network can plausibly alter circulating 25(OH)D levels. The exact mechanistic link between AMDHD1 activity and vitamin D regulation remains under active investigation; GWAS identifies the association but does not establish the precise causal pathway.

The Evidence

The AMDHD1 locus was identified as a novel discovery in a major GWAS by Jiang et al. 2018⁵⁵ GWAS by Jiang et al. 2018
Jiang X, O'Reilly PF, Aschard H, et al. Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels. Nat Commun, 2018 — one of two new loci identified when the SUNLIGHT Consortium expanded its discovery sample from 16,125 to 79,366 European-ancestry individuals. The association at rs10745742 reached P = 1.9×10⁻¹⁴, well beyond the genome-wide significance threshold of 5×10⁻⁸. The T allele was the effect allele associated with higher circulating 25-hydroxyvitamin D, with an effect size of approximately 0.019 standard deviations per allele in inverse-normal transformed 25(OH)D (equivalent to roughly 1–2 nmol/L per T allele in absolute terms).

The signal has been replicated in substantially larger datasets. A UK Biobank GWAS⁶⁶ UK Biobank GWAS
Manousaki D et al. Am J Hum Genet, 2020 in 401,460 participants identified 69 independent vitamin D loci — AMDHD1 among them. A parallel GWAS of 417,580 Europeans⁷⁷ GWAS of 417,580 Europeans
Revez JA et al. Nat Commun, 2020 confirmed 143 loci for 25(OH)D, with the AMDHD1 signal replicated. The consistent appearance of this locus across large independent cohorts upgrades the evidence from discovery-level to replicated-strong, even though the biological mechanism is not yet fully resolved.

The T allele is markedly more common in African-ancestry populations (~64%) than in European populations (~38%), creating a population-stratified pattern where Europeans disproportionately carry the C (lower-D) allele at this locus.

Practical Implications

Carriers of the CC genotype (the most common European genotype) have a modest genetic tendency toward lower circulating vitamin D from this locus alone, though the per-allele effect (~1–2 nmol/L) is smaller than the major vitamin D loci such as DHCR7 or CYP2R1. Effects compound when multiple vitamin D pathway variants co-occur — individuals carrying low-D alleles at AMDHD1, DHCR7, CYP2R1, and GC simultaneously can show substantially reduced 25(OH)D. Standard vitamin D monitoring and judicious supplementation remain the most effective countermeasures.

Interactions

The four classical vitamin D pathway loci each operate at distinct steps: DHCR7 (rs12785878) controls substrate availability for skin synthesis; CYP2R1 (rs10741657) performs liver 25-hydroxylation; GC (rs2282679, rs7041, rs4588) encodes the transport protein; CYP24A1 (rs6013897) degrades active vitamin D. AMDHD1 appears to act upstream through a metabolic support pathway. Since the mechanisms are distinct and additive, polygenic vitamin D risk scores that combine these loci are more informative than any single variant in isolation. A combined genetic risk score across these loci can predict vitamin D insufficiency odds up to 2.5-fold.