rs2073067 — MTHFD1L MTHFD1L variant

MTHFD1L — The Mitochondrial Formate Factory

Most people have heard of MTHFR, but the folate cycle runs on two tracks: the cytoplasmic pathway (where MTHFR operates) and the mitochondrial pathway, where MTHFD1L ¹¹ Methylenetetrahydrofolate dehydrogenase 1-like; the mitochondrial counterpart to the cytoplasmic MTHFD1 enzyme does the foundational work. MTHFD1L converts mitochondrial 10-formyl-THF into formate, which then crosses into the cytoplasm to fuel purine synthesis, thymidylate production, and ultimately the methylation cycle that generates S-adenosylmethionine²² S-adenosylmethionine
SAM: the universal methyl donor used in hundreds of cellular reactions. When MTHFD1L function is altered, the cytoplasmic folate pathway is starved of raw material even when dietary folate appears adequate.

rs2073067 is an intronic variant in MTHFD1L, located on chromosome 6q25.1. Because it falls within an intron, it does not directly change the enzyme's amino acid sequence. Instead, it likely tags a regulatory or splicing haplotype that modulates how much functional enzyme is produced or how efficiently the mitochondrial one-carbon pathway runs.

The Mechanism

MTHFD1L is a monofunctional enzyme that catalyzes a single step: the conversion of 10-formyl-THF to formate using the reversible reaction in the mitochondrial matrix. This formate serves as the primary source of cytoplasmic one-carbon units in most cell types. Without it, the methylation cycle loses throughput, homocysteine can accumulate, and purine synthesis — essential for dividing cells — is impaired.

Mouse models provide the starkest evidence of this pathway's importance: complete Mthfd1l deletion³³ complete Mthfd1l deletion
Momb et al., PNAS 2013 — all Mthfd1l-null embryos exhibited craniorachischisis and exencephaly causes universal neural tube defects (craniorachischisis and exencephaly), and these defects are partially rescued by maternal formate supplementation — confirming that reduced formate output, not simply folate deficiency, underlies the pathology. In humans, a separate MTHFD1L splicing variant (rs3832406) that alters the ratio of long to short transcripts is independently associated with neural tube defect risk⁴⁴ is independently associated with neural tube defect risk
Parle-McDermott et al., Hum Mutat 2009.

The rs2073067 G allele is intronic and likely tags a haplotype affecting MTHFD1L expression or splicing efficiency. Studies show MTHFD1L genetic variation influences both plasma homocysteine and global genomic methylation⁵⁵ plasma homocysteine and global genomic methylation
Wernimont et al., 2011 — MTHFD1L showed pleiotropy for both phenotypes across 330 SNPs in 52 folate-pathway genes, consistent with reduced mitochondrial one-carbon output feeding back to impair cytoplasmic methylation capacity.

The Evidence

rs2073067 was first identified in a GWAS of late-onset Alzheimer's disease⁶⁶ GWAS of late-onset Alzheimer's disease
Naj AC et al. PLoS Genetics 2010 — discovery + replication cohorts totaling ~1,800 cases and 2,500 controls that used MTHFD1L as a chromosome 6 locus providing genetic evidence for folate-pathway abnormalities in neurodegeneration. The primary lead SNP was rs11754661, but rs2073067 showed nominally significant association (P=0.03) as part of the same locus.

A replication study in Northern Han Chinese⁷⁷ replication study in Northern Han Chinese
Ma XY et al. J Alzheimers Dis 2012, n=1,189 found that rs2073067 showed a strikingly protective effect in APOE ε4 carriers specifically (OR = 0.40, p < 0.001), suggesting the variant modulates Alzheimer's risk in a genetic background sensitive to folate-homocysteine metabolism. The haplotype containing rs2073067 and rs11754661 ("AC") conferred increased risk overall (OR = 1.73). This heterogeneity — protective in one allelic context, risk-increasing in another — is characteristic of complex LD patterns in intronic regulatory variants.

The folate-pathway connection is mechanistically plausible: elevated homocysteine is a well-established risk factor for cognitive decline and Alzheimer's disease, and MTHFD1L variation influencing formate output would propagate through homocysteine re-methylation efficiency to affect long-term neurological health.

At the population level, the G allele frequency is approximately 37% in Europeans and 22% in East Asians, making the GG genotype present in roughly 10-12% of most populations — a substantial minority with potential benefit from targeted B-vitamin support.

Practical Implications

Because rs2073067 is intronic and the precise functional mechanism is not yet characterised, the evidence for specific interventions derives from the broader biology of MTHFD1L and mitochondrial one-carbon metabolism. The key targets are: supporting adequate formate supply to the cytoplasm (via B-vitamin cofactors that sustain the mitochondrial pathway), ensuring homocysteine does not accumulate, and monitoring markers of methylation capacity. Active-form B vitamins — particularly methylcobalamin (B12) and methylfolate rather than folic acid — bypass any upstream conversion bottlenecks and directly support the methionine re-methylation that keeps homocysteine in check.

Interactions

MTHFD1L operates upstream of MTHFR (rs1801133 and rs1801131). Individuals with reduced MTHFD1L output AND impaired MTHFR activity face a compounded reduction in methylation capacity: the mitochondrial pathway provides less formate to the cytoplasm, and the cytoplasmic pathway then converts less of that formate to methylfolate. The MTHFD1L rs6922269 variant is separately associated with active vitamin B12 levels and cardiovascular survival in coronary artery disease patients (PMID 24618918), confirming that multiple independent MTHFD1L variants influence metabolic outcomes. The folate transporter SLC19A1 (rs1051266) and methionine synthase reductase MTRR (rs1801394) are additional pathway partners where combined genetic burden amplifies one-carbon insufficiency.