rs123187 (CKM): ERCC2 and KLC3 Expression QTL
Key takeaways
- This variant reduces ERCC2 expression in skin while increasing KLC3 expression in multiple brain regions.
- KLC3 brain effects span the anterior cingulate cortex, general cortex, caudate basal ganglia, and nucleus accumbens basal ganglia.
- Both expression effects are confirmed in GTEx data from 953 donors at genome-wide significance.
- None of the large-scale genome-wide association studies provided identified rs123187 as a lead signal for Alzheimer's disease or cardiovascular traits.
Key takeaways
- This variant reduces ERCC2 expression in skin while increasing KLC3 expression in multiple brain regions.
- KLC3 brain effects span the anterior cingulate cortex, general cortex, caudate basal ganglia, and nucleus accumbens basal ganglia.
- Both expression effects are confirmed in GTEx data from 953 donors at genome-wide significance.
- None of the large-scale genome-wide association studies provided identified rs123187 as a lead signal for Alzheimer's disease or cardiovascular traits.
What the research says GTEx v11 expression quantitative trait locus (eQTL) analysis - a method that links genetic variants to changes in gene activity - across 953 donors shows that rs123187 is significantly associated with reduced ERCC2 (excision repair cross-complementation group 2, a gene involved in DNA nucleotide excision repair) expression in sun-exposed and non-sun-exposed skin GTEx Portal. The same variant is linked to increased KLC3 (kinesin light chain 3, a gene involved in cellular transport along microtubules) expression in several brain regions - including the anterior cingulate cortex, cortex, caudate basal ganglia, and nucleus accumbens basal ganglia - as well as in both skin tissue types GTEx Portal. Three large genome-wide association studies provided as contextual source material, covering Alzheimer's disease and cardiovascular traits across cohorts totalling up to 455,258 individuals, do not specifically name rs123187 among their reported lead variants.
Reported associations
- ERCC2 expression in sun-exposed skin: The alternate allele is linked to reduced ERCC2 expression in sun-exposed lower leg skin (effect slope −0.30) GTEx Portal.
- ERCC2 expression in non-sun-exposed skin: The alternate allele is also linked to reduced ERCC2 expression in non-sun-exposed suprapubic skin (slope −0.27) GTEx Portal.
- KLC3 expression in brain: The alternate allele is linked to increased KLC3 expression in the anterior cingulate cortex (slope +0.50), general cortex (slope +0.44), caudate basal ganglia (slope +0.42), and nucleus accumbens basal ganglia (slope +0.36) GTEx Portal.
- KLC3 expression in skin: The alternate allele is linked to increased KLC3 expression in non-sun-exposed suprapubic skin (slope +0.22) and sun-exposed lower leg skin (slope +0.16) GTEx Portal.
Evidence quality The GTEx v11 eQTL signals for rs123187 are statistically robust across 953 donors: ERCC2 skin effects reach p = 3.1×10^-²³ (sun-exposed skin) and p = 1.9×10^-¹^6 (non-sun-exposed skin); KLC3 brain effects range from p = 5.4×10^-¹^0 to p = 3.6×10^-9, and KLC3 skin effects reach p = 1.0×10^-²^7 and p = 8.6×10^-²^6 GTEx Portal. These are mechanism-level expression findings, not direct clinical outcome data. Three provided genome-wide studies - one identifying 16 shared Alzheimer's disease and cardiovascular loci via multi-trait analysis, one identifying 246 loci in Alzheimer's disease polygenic risk score extremes (n = 377,834 UK Biobank participants), and one meta-analysis of 455,258 individuals identifying 29 Alzheimer's disease risk loci - did not specifically report rs123187 as a lead variant in the available text. The overall evidence base for this variant is therefore limited to tissue-specific expression effects, with no replication of disease associations available from the provided sources.
Tissue-specific expression effects
- ERCC2: Reduced expression in both sun-exposed lower leg skin and non-sun-exposed suprapubic skin in carriers of the alternate allele GTEx Portal.
- KLC3: Increased expression in the anterior cingulate cortex, general cortex, caudate basal ganglia, and nucleus accumbens basal ganglia (brain), as well as in non-sun-exposed suprapubic and sun-exposed lower leg skin GTEx Portal.
Lifestyle considerations No lifestyle considerations on file for this variant.
Frequently asked questions
What does rs123187 do?
rs123187 affects the activity of two genes: it reduces ERCC2 expression in skin tissue and increases KLC3 expression in several brain regions and skin. These are gene-regulation changes at the expression level, not established disease risk associations based on the available evidence.
What gene is rs123187 near?
rs123187 is located in the CKM-RPS16P9 region, near the creatine kinase muscle gene (CKM) and a ribosomal protein pseudogene (RPS16P9). Its documented expression effects are on ERCC2 and KLC3, which lie in the same chromosomal neighbourhood.
Is rs123187 linked to Alzheimer's disease?
Three large genome-wide association studies covering Alzheimer's disease and cardiovascular traits were provided as context for this entry, but none specifically identified rs123187 as a lead variant. Current evidence for this variant is limited to gene expression effects in skin and brain tissue.
What brain areas does rs123187 affect?
According to GTEx v11 data, the alternate allele at rs123187 is linked to increased KLC3 expression in the anterior cingulate cortex, general cortex, caudate basal ganglia, and nucleus accumbens basal ganglia. These are association signals at the gene-expression level, not structural or functional changes in the brain.
What is ERCC2 and why does its expression matter?
ERCC2 is a gene involved in nucleotide excision repair, a cellular process that corrects certain types of DNA damage. rs123187 is associated with reduced ERCC2 expression in skin tissue, though the clinical significance of this expression change is not established in the available studies.