rs4446909 — ASMT Promoter A>G

ASMT Promoter Variant -- Your Melatonin Production Blueprint

The ASMT gene encodes acetylserotonin O-methyltransferase¹¹ acetylserotonin O-methyltransferase
Also called hydroxyindole O-methyltransferase (HIOMT), this enzyme adds a methyl group to N-acetylserotonin using SAMe as the methyl donor, the enzyme that catalyzes the final step in melatonin biosynthesis²² melatonin biosynthesis
The pathway runs: tryptophan -> serotonin -> N-acetylserotonin (via AANAT) -> melatonin (via ASMT). Without functional ASMT, your body cannot complete the conversion of serotonin-derived intermediates into melatonin -- the hormone that signals darkness to your brain, lowers core body temperature, and initiates sleep onset.

rs4446909 sits in the ASMT promoter region, 207 base pairs upstream of the transcription start site within a CCCAC box³³ CCCAC box
A regulatory DNA motif involved in controlling how much mRNA is produced from the gene. The G allele at this position reduces transcription of the ASMT gene, meaning less enzyme is produced and less melatonin is synthesized. ASMT is located in the pseudoautosomal region 1 (PAR1)⁴⁴ pseudoautosomal region 1 (PAR1)
A region at the tips of the X and Y chromosomes that recombines during meiosis just like autosomes, so it is inherited in a non-sex-linked pattern despite being on the sex chromosomes of the X and Y chromosomes, which means both men and women carry two copies and inheritance follows a standard autosomal pattern.

The Mechanism

ASMT transfers a methyl group from S-adenosylmethionine (SAMe)⁵⁵ S-adenosylmethionine (SAMe)
The universal methyl donor in human biochemistry, produced from methionine and ATP to N-acetylserotonin, producing melatonin. The enzyme is primarily expressed in the pineal gland, retina, and brain, with peak activity during darkness as part of the circadian cycle. The rs4446909 G allele disrupts promoter activity at the CCCAC box, reducing ASMT mRNA transcription. In lymphoblastoid cell lines⁶⁶ lymphoblastoid cell lines
Immortalized B cells used as a laboratory model for studying gene expression, the GG genotype is associated with dramatically lower ASMT transcript levels -- by a factor of 4 to 20 compared to the AA genotype -- and correspondingly reduced enzymatic activity.

Because ASMT catalyzes the terminal step in melatonin production, reduced enzyme levels create a bottleneck. N-acetylserotonin accumulates while melatonin output drops. This is distinct from upstream pathway disruptions (such as AANAT variants) because the substrate is available but cannot be efficiently converted to the final product.

The Evidence

The foundational study by Melke et al. (2008)⁷⁷ Melke et al. (2008)
Melke J et al. Abnormal melatonin synthesis in autism spectrum disorders. Mol Psychiatry, 2008 first characterized rs4446909 as a functional promoter variant. In 278 individuals with autism spectrum disorder and 255 controls, the G allele was significantly more frequent in ASD (0.77 vs 0.70, P=0.006, OR=1.5). The study found a highly significant decrease in ASMT activity (P=2x10^-12) and melatonin levels (P=3x10^-11) in ASD individuals, with the G allele genotypes showing the lowest ASMT transcript levels (P=2x10^-8).

Etain et al. (2012)⁸⁸ Etain et al. (2012)
Etain B et al. Genetic and functional abnormalities of the melatonin biosynthesis pathway in patients with bipolar disorder. Hum Mol Genet, 2012 replicated the association in bipolar disorder, finding significant association with rs4446909 in a discovery sample (P=0.01) confirmed in 480 independent patients and 672 controls (P=0.002). The GG genotype was linked to lower ASMT mRNA and reduced enzymatic activity compared to controls (P=0.001).

A follow-up by Geoffroy et al. (2014)⁹⁹ Geoffroy et al. (2014)
Geoffroy PA et al. An ASMT variant associated with bipolar disorder influences sleep and circadian rhythms: a pilot study. Genes Brain Behav, 2014 studied 53 subjects (25 bipolar patients in remission, 28 controls) and found the GG genotype was associated with longer sleep duration (P=0.03), greater activity during sleep periods (P=0.015), and greater interday circadian stability (P=0.003).

In recurrent depression, Galecki et al. (2010)¹⁰¹⁰ Galecki et al. (2010)
Galecki P et al. SNPs and mRNA expression for melatonin synthesis rate-limiting enzyme in recurrent depressive disorder. J Pineal Res, 2010 found the AA genotype was protective against depression in 181 patients versus 149 controls, while the GG genotype was associated with lower ASMT mRNA expression in both patients and controls.

Practical Implications

The clinical relevance of rs4446909 centers on melatonin production capacity. If you carry one or two G alleles, your baseline melatonin synthesis may be lower than optimal, potentially contributing to difficulty with sleep onset, lighter sleep in the first half of the night, or a tendency to feel alert later into the evening than desired.

Exogenous melatonin supplementation can compensate for reduced endogenous production. Low-dose melatonin (0.3-1 mg) taken 30-60 minutes before desired sleep time most closely mimics physiological melatonin release. Higher doses (3-5 mg) are commonly sold but may cause morning grogginess and are not necessarily more effective for sleep onset.

Supporting the upstream pathway also matters: adequate tryptophan¹¹¹¹ tryptophan
The amino acid precursor to serotonin, found in turkey, eggs, cheese, nuts, and seeds intake provides the raw material, while the methylation cycle must supply sufficient SAMe for ASMT to function. Bright light exposure in the morning and dim light in the evening help calibrate the circadian signal that drives pineal ASMT expression.

Interactions

rs4446909 is in strong linkage disequilibrium (D'=0.94) with rs5989681, another ASMT promoter variant located 97 bp upstream in a putative NF-kappaB binding site. These two SNPs tend to be inherited together and have concordant effects on ASMT expression. Most studies that find an association with rs4446909 also find it with rs5989681.

The melatonin synthesis pathway involves two enzymatic steps after serotonin: AANAT (serotonin -> N-acetylserotonin) and ASMT (N-acetylserotonin -> melatonin). Variants in AANAT could compound the effect of ASMT variants by reducing substrate availability, though this interaction is less well characterized than the ASMT promoter variants themselves.

ASMT requires SAMe as a methyl donor, creating a functional link to the methylation cycle. Variants affecting methylation capacity (such as MTHFR C677T) could theoretically compound ASMT insufficiency by limiting SAMe availability, though direct evidence for this gene-gene interaction on melatonin levels is not yet established.