rs12091750 (PLEKHM2): Cardiovascular and Brain eQTL Variant
Key takeaways
- rs12091750 is a variant near PLEKHM2 (Pleckstrin Homology and RUN Domain Containing M2), identified in the context of a large multi-trait cardiovascular genomics study
- The alternate allele increases PLEKHM2 expression in brain cerebellar regions while decreasing it in esophageal tissue, a directionally opposite pattern across two organ systems
- Three nearby genes, SLC25A34, AGMAT, and DDI2, also show reduced expression linked to this variant across esophageal, thyroid, tibial nerve, pancreatic, and fibroblast tissues
- The cardiovascular study contextualizing this locus used MTAG (multi-trait analysis of GWAS), a method that improves statistical power by jointly analyzing genetically correlated traits
Key takeaways
- rs12091750 is a variant near PLEKHM2 (Pleckstrin Homology and RUN Domain Containing M2), identified in the context of a large multi-trait cardiovascular genomics study
- The alternate allele increases PLEKHM2 expression in brain cerebellar regions while decreasing it in esophageal tissue, a directionally opposite pattern across two organ systems
- Three nearby genes, SLC25A34, AGMAT, and DDI2, also show reduced expression linked to this variant across esophageal, thyroid, tibial nerve, pancreatic, and fibroblast tissues
- The cardiovascular study contextualizing this locus used MTAG (multi-trait analysis of GWAS), a method that improves statistical power by jointly analyzing genetically correlated traits
What the research says A 2025 study published in NPJ Genomic Medicine applied MTAG across 58 cardiovascular traits and diseases, identifying 19 novel loci for atrial fibrillation (AF), 131 novel loci for coronary artery disease (CAD), and 141 novel loci for heart failure (HF); polygenic scores derived from this analysis were validated in 15,177 Canadian individuals, and MTAG-based scores improved CAD prediction and reclassification specifically in females, with a gain in explained variance of approximately 1.74% (95% CI: 0.61-2.86) and a net reclassification index of 0.208 (95% CI: 0.139-0.277). GTEx v11 eQTL analysis from 953 donors shows that rs12091750 is significantly associated with altered expression of PLEKHM2 and three additional neighboring genes across brain, esophageal, thyroid, tibial nerve, pancreatic, and fibroblast tissue types GTEx Portal.
Reported associations
- PLEKHM2 expression - brain cerebellar hemisphere: The alternate allele is associated with increased expression (effect +0.61 log2 units, p=1.1e-37, GTEx v11, n=953 donors) GTEx Portal
- PLEKHM2 expression - cerebellum: The alternate allele is associated with increased expression (+0.54 log2 units, p=1.3e-27) GTEx Portal
- PLEKHM2 expression - esophageal mucosa: The alternate allele is associated with decreased expression (-0.27 log2 units, p=6.8e-34) GTEx Portal
- SLC25A34 expression: The alternate allele is associated with reduced expression in esophageal mucosa (-0.34 log2 units, p=4.4e-18), thyroid (-0.33, p=2.2e-17), and tibial nerve (-0.30, p=1.5e-14) GTEx Portal
- AGMAT expression - pancreas: The alternate allele is associated with reduced expression (-0.47 log2 units, p=6.1e-12) GTEx Portal
- DDI2 expression - cultured fibroblasts: The alternate allele is associated with reduced expression (-0.22 log2 units, p=7.4e-20) GTEx Portal
- Cardiovascular locus: rs12091750 appears in a 2025 multi-trait genomics study analyzing loci for AF, CAD, and HF across 58 cardiovascular phenotypes
Evidence quality The GTEx eQTL associations (v11, 953 donors, FDR < 0.05) show strong statistical evidence across multiple tissues, with p-values ranging from 1.1e-37 for PLEKHM2 in cerebellar hemisphere to 6.1e-12 for AGMAT in pancreas GTEx Portal. The cardiovascular GWAS/MTAG study validated polygenic scores in 15,177 Canadian individuals, but the available study text does not explicitly specify which cardiovascular disease category rs12091750 is most strongly associated with, limiting disease-specific interpretation for this variant. No independent replication study specific to this variant is included among the provided sources. The eQTL evidence is statistically robust across six distinct tissue types; the clinical significance of these expression changes in relation to cardiovascular disease outcomes remains to be established from the current evidence base.
Tissue-specific expression effects
- PLEKHM2: The alternate allele is associated with increased expression in brain cerebellar hemisphere and cerebellum, and with reduced expression in esophageal mucosa, showing directionally opposite regulation across brain and digestive tissue GTEx Portal
- SLC25A34: The alternate allele is associated with reduced expression in esophageal mucosa, thyroid, and tibial nerve GTEx Portal
- AGMAT: The alternate allele is associated with reduced expression in pancreas GTEx Portal
- DDI2: The alternate allele is associated with reduced expression in cultured fibroblasts GTEx Portal
Lifestyle considerations No lifestyle considerations on file for this variant.
Frequently asked questions
What is PLEKHM2?
PLEKHM2, short for Pleckstrin Homology and RUN Domain Containing M2, is a gene whose expression is influenced by the rs12091750 variant. GTEx data show the alternate allele increases PLEKHM2 expression in brain cerebellar regions while decreasing it in esophageal tissue.
Is rs12091750 linked to heart disease?
This variant appears in research examining genetic loci for cardiovascular conditions including atrial fibrillation, coronary artery disease, and heart failure. A 2025 study used MTAG to jointly analyze 58 cardiovascular traits, identifying over 290 novel loci across those three conditions, but the specific disease association for rs12091750 alone is not detailed in the available study text.
What does rs12091750 do to gene expression in the brain?
According to GTEx v11 data from 953 donors, the alternate allele of rs12091750 is associated with increased PLEKHM2 expression in both the cerebellar hemisphere (effect +0.61, p=1.1e-37) and the cerebellum (effect +0.54, p=1.3e-27). These are among the strongest eQTL signals reported for this variant.
What is MTAG and why does it matter for this variant?
MTAG, or multi-trait analysis of GWAS, is a statistical method that boosts the power to detect genetic associations by jointly analyzing traits that share a genetic basis. The 2025 cardiovascular study used this approach across 58 traits and diseases, improving the ability to find loci for atrial fibrillation, coronary artery disease, and heart failure.
Which other genes near rs12091750 show expression changes?
Beyond PLEKHM2, GTEx data show the alternate allele of rs12091750 is associated with reduced expression of SLC25A34 in esophageal mucosa, thyroid, and tibial nerve, reduced AGMAT expression in pancreas, and reduced DDI2 expression in cultured fibroblasts.