Expressive

rs11771145 (EPHA1): Alzheimer's Disease Risk Variant

Key takeaways

  • The minor A allele (~35% frequency) is associated with slightly lower late-onset Alzheimer's disease risk (odds ratio ~0.95)
  • Confirmed across multiple studies totaling more than 700,000 participants from European and multi-ancestry cohorts
  • The A allele is linked to increased expression of EPHA1-AS1 across several tissues, most strongly in whole blood and spleen
  • The individual effect is modest; this variant is one of dozens of common signals that together influence Alzheimer's disease risk
  • Some data suggest broadly similar genetic effects in admixed Latin American populations

Key takeaways

  • The minor A allele of rs11771145 (frequency ~35% in European populations) is associated with slightly reduced late-onset Alzheimer's disease risk (odds ratio ~0.95)
  • This association has been confirmed across multiple studies totaling more than 700,000 participants, including multi-ancestry cohorts
  • The A allele is also linked to increased expression of EPHA1-AS1 across several tissues, most strongly in whole blood and spleen
  • The individual effect is modest; this variant is one of dozens of common signals that together influence Alzheimer's disease risk
  • Some data suggest broadly similar genetic effects in admixed Latin American populations

What the research says

rs11771145 sits at chromosome 7 position 143,413,669 within the EPHA1 (EPHA1-AS1) locus. A two-stage meta-analysis totaling 17,008 cases and 37,154 controls in stage 1, followed by independent genotyping of 8,572 cases and 11,312 controls in stage 2, first identified this locus among 11 newly significant Alzheimer's disease (AD) susceptibility signals PMID 24162737. A larger analysis of 111,326 clinically diagnosed or proxy AD cases and 677,663 controls confirmed the minor A allele carries an odds ratio of 0.95 (95% CI 0.93-0.96, P = 3.3 × 10^-¹^4), listing the region among robustly replicated known risk loci PMID 35379992. A multi-ancestry meta-analysis extending to East Asian, African American, and Caribbean Hispanic cohorts (54,233 AD cases, 46,828 proxy-dementia cases, 543,127 controls) further assessed heterogeneity and fine-mapping across established AD loci including this one PMID 36702997.

Reported associations

  • Alzheimer's disease (late-onset risk): Minor A allele associated with reduced risk; OR = 0.95 (95% CI 0.93-0.96), P = 3.3 × 10^-¹^4, in 111,326 cases and 677,663 controls PMID 35379992
  • Alzheimer's disease (late-onset risk): One of 11 newly identified AD susceptibility loci in a two-stage European-ancestry meta-analysis totaling 25,580 cases across both stages PMID 24162737
  • Alzheimer's disease (late-onset risk): Confirmed among 29 genome-wide significant loci in a meta-analysis of 71,880 cases and 383,378 controls that incorporated an AD-by-proxy phenotype derived from parental diagnoses PMID 30617256
  • Alzheimer's disease (family history proxy): Assessed among known AD loci in a proxy-phenotype GWAS meta-analysis of 314,278 UK Biobank participants reporting parental AD history PMID 31695033
  • Alzheimer's disease (clinical endophenotypes): Assessed across dementia clinical subgroups defined by clinical certainty and vascular burden in the GR@ACE project PMID 32073218

Evidence quality

The EPHA1 locus has reached genome-wide significance (P < 5 × 10^-8) in multiple independent studies PMID 24162737; PMID 30617256; PMID 35379992, with the most precise effect estimate (OR = 0.95, P = 3.3 × 10^-¹^4) derived from the largest available meta-analysis of over 788,000 participants PMID 35379992. Evidence is predominantly from European-ancestry populations; a multi-ancestry study extended assessment to four super-populations PMID 36702997, and the first GWAS conducted in Argentina and Chile found that European-derived AD genetic risk scores perform comparably in admixed Latin American populations, though predictive performance decreases as Native American ancestry proportion increases PMID 38409848. No conflicting directional findings are reported across any of the reviewed studies. The absolute effect size is modest, consistent with the polygenic architecture of late-onset AD.

Tissue-specific expression effects

  • EPHA1-AS1: The A allele is associated with increased expression in whole blood (largest effect), spleen, tibial nerve, subcutaneous adipose tissue, lung, and visceral adipose tissue GTEx Portal
  • TAS2R60: The A allele is associated with increased expression in whole blood GTEx Portal
  • ENSG00000309493: The A allele is associated with increased expression in whole blood GTEx Portal

Lifestyle considerations

No lifestyle considerations on file for this variant.

Frequently asked questions

What gene is rs11771145 associated with?

rs11771145 is located within the EPHA1 locus on chromosome 7. The variant also influences expression of EPHA1-AS1, a neighboring gene, across multiple tissues including whole blood and spleen.

Is rs11771145 linked to Alzheimer's disease?

Yes. The minor A allele at rs11771145 is associated with a modestly reduced risk of late-onset Alzheimer's disease (odds ratio ~0.95, P = 3.3 × 10^-¹^4). This finding has been replicated in multiple independent studies totaling hundreds of thousands of participants.

How large is the effect of rs11771145 on Alzheimer's risk?

The odds ratio of approximately 0.95 for the minor A allele is statistically robust but modest in absolute terms. For comparison, APOE ε4, the strongest common AD risk factor, carries an odds ratio above 2 in the same studies. rs11771145 is one of dozens of common variants that collectively contribute to AD risk.

Which tissues does rs11771145 affect gene expression in?

GTEx data show the A allele is associated with increased EPHA1-AS1 expression in whole blood (largest effect), spleen, tibial nerve, subcutaneous and visceral adipose tissue, and lung. The same allele is also linked to increased TAS2R60 expression in whole blood.

Has rs11771145 been studied in non-European populations?

Yes. A multi-ancestry meta-analysis examined this locus across European, East Asian, African American, and Caribbean Hispanic populations. A separate GWAS in Argentina and Chile found that European-derived AD genetic risk scores perform comparably in admixed Latin American populations, though predictive performance decreases as Native American ancestry increases.