rs2075650
badMag 6.5This is a intron variant variant in the TOMM40 gene.
Key Literature Trait Associations
Alzheimer's Disease Risk
The rs2075650 variant in TOMM40 (translocase of the outer mitochondrial membrane 40) is located in the APOE-TOMM40-APOC1 gene cluster and is in strong linkage disequilibrium with the APOE ε4 allele (rs429358). A meta-analysis of 8 studies (4,290 AD cases, 5,556 controls) found the G allele significantly associated with Alzheimer's disease in European and Korean populations. IMPORTANT: The large odds ratio primarily reflects LD with APOE ε4 rather than an independent TOMM40 effect. Conditional analyses adjusting for APOE suggest much of the signal is driven by rs429358. The independent TOMM40 contribution remains debated.
Longevity
The rs2075650 G allele is associated with reduced likelihood of surviving to very old age. A GWAS meta-analysis involving 4,149 nonagenarians and 7,582 younger controls found OR=0.71 (95% CI 0.65–0.77, p=3.39×10⁻¹⁷) for carriers surviving to 90+, indicating the G allele is substantially depleted among long-lived individuals. A 2022 systematic review of 24 studies confirmed rs2075650 as one of the two most-studied TOMM40 SNPs in longevity research, with documented effects on BMI, brain integrity, cognitive function, and inflammatory markers. The longevity effect likely reflects, at least in part, the allele's co-inheritance with APOE ε4.
LDL cholesterol
The rs2075650 G allele in TOMM40 has been associated with elevated LDL cholesterol across multiple populations. A Japanese case-control study (n=5,460) found OR=1.43 (p=0.0004, dominant model) for dyslipidemia. A study in ethnic Russians identified association with LDL-C in male participants, and earlier work demonstrated that rs2075650 predicts LDL particle buoyancy and may increase small, dense LDL formation — a mechanism plausibly linking it to cardiovascular risk. This association may partly reflect LD with APOE ε4, which is known to elevate LDL cholesterol.
Cardiovascular mortality
A 2024 observational study in 276 advanced atherosclerosis patients found that rs2075650 Xg (G allele) carriers had substantially higher fatal cardiovascular event rates than AA homozygotes (8.2% vs. 4.4%, HR=4.53, 95% CI 1.18–17.37, p=0.04). G allele carriers also showed higher rates of left bundle branch block and underwent cardiac device implantation approximately 7 years earlier. The study was small and observational; these findings require replication but suggest TOMM40 variation may influence cardiovascular prognosis beyond its lipid effects.
Major depressive disorder
Exploratory evidence suggests the rs2075650 G allele may confer vulnerability to major depressive disorder. A three-level study of 1,220 community participants found the G allele significantly associated with lifetime depression (p=0.00006). G allele carriers with depression showed reduced extraversion, executive dysfunction, decreased positive memory bias, and altered neural responses during emotional processing. This association is based on a single candidate-gene study and requires replication in larger cohorts before drawing clinical conclusions.
▶GWAS Catalog Trait Associations (24)
Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.
GWAS Catalog Trait Associations (24)
Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.
▶Research that mentions this SNP (4)
▶Haplotype architecture of the Alzheimer's risk in the
APOE
region via co‐skewnessAssociationN=19,123Alexander M. Kulminski et al.(2020)· Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring
This study examined 4960 SNP triples from five genes in the APOE region (BCAM, NECTIN2, TOMM40, APOE, APOC1) in 2789 Alzheimer's disease cases and 16,334 controls using a novel co-skewness metric to identify complex haplotypes associated with AD. The authors identified 1127 significant AD-associated SNP triples, demonstrating that complex multi-SNP haplotypes—which may not include the canonical APOE ε4 or ε2 alleles—play definitive roles in AD predisposition, with the ε4 allele showing strengthened connections to other region alleles and ε2 showing weakened connections in affected subjects.
▶A Comprehensive Genetic Association Study of Alzheimer Disease in African AmericansAssociationN=1,009Logue MW et al.(2011)· Archives of Neurology
This comprehensive genome-wide association study examined genetic variants contributing to late-onset Alzheimer's disease (AD) in 513 African American cases and 496 controls, plus replication in 5 white cohorts. The APOE ε4 allele showed strong association (P=9.69×10⁻²³), and after adjusting for APOE, rs6859 in PVRL2 remained significantly associated (P=0.0087). The study found associations with variants in CLU, PICALM, BIN1, EPHA1, MS4A, ABCA7, and CD33, though effect directions sometimes differed from white populations. Novel associations with suggestive evidence were identified in PROX1, CNTNAP2, STK24, and other genes, though not replicated in whites.
▶Genome-wide Analysis of Genetic Loci Associated With Alzheimer DiseaseAssociationN=35,000Seshadri S. et al.(2010)· JAMA
This 3-stage genome-wide association meta-analysis study identified 5 novel and confirmed loci associated with late-onset Alzheimer's disease across over 35,000 individuals. The study discovered two new genome-wide significant loci: rs744373 in BIN1 (OR 1.13, p=1.59×10⁻¹¹) and rs597668 near EXOC3L2 (OR 1.18, p=6.45×10⁻⁹), and confirmed three previously reported loci in APOE (OR 2.53, p=1.04×10⁻²⁹⁵), CLU (OR 0.85, p=1.62×10⁻¹⁶), and PICALM (OR 0.89, p=3.16×10⁻¹²). These findings were validated in an independent Spanish replication sample of 2,349 individuals.
▶Extreme cerebrospinal fluid amyloid β levels identify family with late‐onset Alzheimer's disease presenilin 1 mutationReviewJohn S. K. Kauwe et al.(2007)· Annals of Neurology
A review of genetic discoveries in Alzheimer's disease using cerebrospinal fluid (CSF) levels of amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau181) as endophenotypes. The paper discusses multiple GWAS and sequencing studies that identified novel AD risk variants including rs9877502 (3q28, p=4.89×10⁻⁹), rs514716 in GLIS3 (p=1.07×10⁻⁸), and rs6922617 in TREM cluster (p=3.58×10⁻⁸), as well as functional characterization of known AD variants including APOE, MAPT, and TREM2. The review emphasizes the increased statistical power of using quantitative CSF biomarkers compared to traditional case-control designs.
Gene information from NCBI Gene. Variant classifications from ClinVar.
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