rs10865879 (EXOG): Heart Electrical Activity Variant

Key takeaways

• rs10865879, located at the EXOG locus, was identified among 52 genomic regions linked to heart electrical activity in a study of up to 73,518 people
• This variant influences gene expression in heart and brain tissue, based on population-level eQTL data from 953 donors
• Effect sizes found in European-ancestry genetic studies may differ across other populations, a concern raised by a study of 49,839 non-European participants
• The nearby gene ACVR2B-AS1 shows increased expression in both heart and brain tissue in carriers of this variant

What the research says A genome-wide association meta-analysis of four QRS complex traits (electrocardiogram measures reflecting cardiac depolarization and ventricular muscle mass) identified 52 loci including this region at genome-wide significance (p < 1 x 10^-8) in up to 73,518 European-ancestry individuals PMID 27553565. The Population Architecture using Genomics and Epidemiology (PAGE) study examined 26 clinical and behavioral phenotypes in 49,839 non-European participants, identifying 27 novel loci and 38 secondary signals at known loci, and documenting substantial effect-size heterogeneity across ancestries for established GWAS associations PMID 31217584. Expression quantitative trait locus (eQTL) data from GTEx links this variant to altered expression of nearby genes in cardiac and neural tissue GTEx Portal.

Reported associations

• QRS complex traits (cardiac electrical activity): This locus was associated with Sokolow-Lyon voltage, Cornell voltage, 12-lead voltage duration product, and QRS duration in a meta-analysis of up to 73,518 European-ancestry individuals (p < 1 x 10^-8) PMID 27553565
• Multi-ethnic trait architecture: PAGE examined 26 clinical and behavioral traits in 49,839 non-European participants and found evidence that risk allele frequencies and effect sizes at established loci differ across ancestries, with 27 novel loci and 38 secondary signals identified in underrepresented groups PMID 31217584

Evidence quality The cardiac association derives from an inverse-variance fixed-effects meta-analysis combining 24 studies with up to 73,518 European-ancestry individuals, applying a threshold of p < 1 x 10^-8 PMID 27553565. Identified loci, including this one, were enriched in regions of open chromatin, covalently modified histones, and cardiac transcription factor binding sites, providing functional support for biological relevance PMID 27553565. PAGE highlights that European-ancestry GWAS findings may not generalize across all populations; specific effect estimates for this locus in non-European cohorts are not detailed in the available report PMID 31217584. GTEx eQTL data (953 donors, FDR-controlled cis-window analysis) provides mechanistic context at the transcriptional level and is distinct from direct evidence about clinical outcomes GTEx Portal.

Tissue-specific expression effects

• ACVR2B-AS1: This variant is associated with increased expression of ACVR2B-AS1 (an antisense RNA near the activin A receptor type 2B gene) in brain cerebellar hemisphere tissue and in heart atrial appendage tissue GTEx Portal
• XYLB: This variant is associated with reduced expression of XYLB in colon transverse tissue and in cultured fibroblasts GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.