rs12422267 (EP400P1): Plasma Amyloid Beta Levels
Key takeaways
- rs12422267 appeared as a suggestive GWAS signal for plasma amyloid beta peptide levels in 3,528 older European adults.
- The signal did not reach genome-wide significance and has not been independently replicated.
- The alternate allele consistently reduces expression of the EP400P1 pseudogene across seven tissue types, including blood, arteries, and thyroid.
- A nearby RNA-processing gene, DDX51, shows increased expression in fibroblasts when the alternate allele is present.
- Expression effects are robustly established; disease-level associations remain preliminary.
Key takeaways
- rs12422267 appeared as a suggestive GWAS signal for plasma amyloid beta peptide levels in 3,528 older European adults.
- The signal did not reach genome-wide significance and has not been independently replicated.
- The alternate allele consistently reduces expression of the EP400P1 pseudogene across seven tissue types, including blood, arteries, and thyroid.
- A nearby RNA-processing gene, DDX51, shows increased expression in fibroblasts when the alternate allele is present.
- Expression effects are robustly established; disease-level associations remain preliminary.
What the research says A genome-wide association meta-analysis examined plasma concentrations of amyloid beta (Abeta) peptides - protein fragments derived from the amyloid precursor protein (APP) that accumulate in Alzheimer disease brain plaques - in 3,528 healthy older adults of European descent across four cohorts. The analysis identified 18 suggestive loci at p < 1x10-5, among them the region near EP400P1 (a pseudogene with Ensembl ID ENSG00000291171); no locus, including this one, reached genome-wide significance (p < 5x10-8). Separately, expression-QTL (eQTL) data from GTEx, based on 953 donors, show that the alternate allele at this locus is robustly linked to reduced EP400P1 expression across seven tissues and increased expression of DDX51 (DEAD-box helicase 51, an RNA helicase gene) in cultured fibroblasts GTEx Portal.
Reported associations
- Plasma amyloid beta peptide concentrations: This locus appeared among 18 suggestive signals (p < 1x10-5) in a meta-analysis of 3,528 healthy older Europeans studying plasma Abeta1-40 and Abeta1-42 levels; the specific peptide subtype and individual effect size for this locus are not reported in the provided study text.
- EP400P1 expression (multiple tissues): The alternate allele is associated with reduced expression of EP400P1 in aortic artery, tibial artery, thyroid, lung, whole blood, tibial nerve, and cultured fibroblasts, with the largest reduction seen in aortic tissue GTEx Portal.
- DDX51 expression (cultured fibroblasts): The alternate allele is associated with increased DDX51 expression in cultured fibroblasts GTEx Portal.
Evidence quality The plasma Abeta association is preliminary and requires cautious interpretation. The meta-analysis totaled 3,528 participants across four European cohorts and achieved only suggestive significance (p < 1x10-5); genome-wide significance (p < 5x10-8) was not reached at this locus. The strongest individual signal in that study was at CTXN3 (cortexin 3) for Abeta1-42 levels, not at this region. No independent replication of the rs12422267 plasma amyloid signal is described in the provided text. The GTEx eQTL data are considerably more robust: the EP400P1 expression signal survives FDR correction across seven tissues with p-values ranging from approximately 5x10-24 to 4x10-43, and the DDX51 fibroblast signal reaches p = 1.6x10-45 GTEx Portal. eQTL findings describe gene-expression-level associations and do not by themselves establish disease causality.
Tissue-specific expression effects
- EP400P1 (ENSG00000291171): The alternate allele is associated with reduced expression across seven tissues: aortic artery (strongest signal), thyroid, tibial artery, cultured fibroblasts, lung, whole blood, and tibial nerve GTEx Portal.
- DDX51: The alternate allele is associated with increased expression in cultured fibroblasts GTEx Portal.
Lifestyle considerations No lifestyle considerations on file for this variant.
Frequently asked questions
What is EP400P1?
EP400P1 is a pseudogene, meaning it is a DNA segment that resembles a protein-coding gene but is not known to produce a functional protein. It is structurally related to EP400, a gene involved in regulating how DNA is packaged inside cells.
Is rs12422267 linked to Alzheimer disease?
A genome-wide association study identified the region near rs12422267 as a suggestive signal for plasma amyloid beta peptide levels, which are a research biomarker related to Alzheimer disease. However, the association did not reach genome-wide significance and has not been independently replicated, so any link remains preliminary.
What does rs12422267 do to gene expression?
According to GTEx data, the alternate allele at rs12422267 is associated with reduced expression of EP400P1 across seven tissue types, including blood, lung, thyroid, and both aortic and tibial arteries. The same allele is associated with increased expression of DDX51, an RNA-processing gene, in cultured fibroblasts.
What are amyloid beta peptides?
Amyloid beta peptides are small protein fragments produced when the amyloid precursor protein is cut by enzymes called secretases. At abnormal concentrations they aggregate into plaques in the brain, a hallmark of Alzheimer disease, though they are also present throughout the body and have normal biological functions at physiological levels.
What is an eQTL?
An expression quantitative trait locus (eQTL) is a genetic variant statistically associated with differences in the activity level of a nearby gene. eQTLs help researchers understand how DNA variation influences which genes are turned up or down in specific tissues, though they do not directly prove disease causation.