rs1015451 (GJA1 region): Resting Heart Rate Variant
Key takeaways
- rs1015451 sits near GJA1, confirmed in a 181,171-person genome-wide study as one of seven established heart rate gene regions.
- The seven confirmed loci together account for about 0.7% of resting heart rate variation; each individual variant carries a modest effect.
- Both faster and slower heart rate versions of variants at this locus are independently linked to changed atrial fibrillation risk.
- Heart rate-raising variants here are also associated with lower risk of sick sinus syndrome, a pacemaker disorder.
- GTEx data show rs1015451 affects GJA1 gene activity in tibial nerve and influences other genes in skin, artery, fat, and testis tissue.
Key takeaways
- rs1015451 sits near GJA1, confirmed in a 181,171-person genome-wide study as one of seven established heart rate gene regions.
- The seven confirmed loci together account for about 0.7% of resting heart rate variation; each individual variant carries a modest effect.
- Both faster and slower heart rate versions of variants at this locus are independently linked to changed atrial fibrillation risk.
- Heart rate-raising variants here are also associated with lower risk of sick sinus syndrome, a pacemaker disorder.
- GTEx data show rs1015451 affects GJA1 gene activity in tibial nerve and influences other genes in skin, artery, fat, and testis tissue.
What the research says A two-stage meta-analysis of genome-wide association studies (GWAS, meaning studies that simultaneously scan hundreds of thousands of genetic markers across the genome) in up to 181,171 individuals confirmed the region near GJA1, flanked by two non-coding pseudogenes (RPL23AP48 and HMGB3P18 - gene-like sequences that do not produce functional proteins), as one of seven previously established loci for resting heart rate, with associations reaching genome-wide significance (P < 5 x 10^-8). The seven confirmed loci together explain approximately 0.7% of resting heart rate variance, indicating that each individual locus carries a modest effect. Genetic susceptibility to higher heart rate at these loci was also associated with altered cardiac conduction (the electrical signals that coordinate each heartbeat), reduced risk of sick sinus syndrome (a disorder of the heart's pacemaker region), and modified risk of atrial fibrillation (an irregular rhythm in the upper heart chambers).
Reported associations
- Resting heart rate: The locus near GJA1 (encompassing RPL23AP48 and HMGB3P18) was one of seven previously established regions confirmed at genome-wide significance (P < 5 x 10^-8) in a meta-analysis of up to 181,171 individuals; the seven confirmed loci together explain approximately 0.7% of heart rate variance.
- Cardiac conduction: Genetic susceptibility to increased heart rate at this locus is associated with altered patterns of cardiac electrical conduction.
- Sick sinus syndrome: Heart rate-increasing variants at this locus are associated with reduced risk of sick sinus syndrome.
- Atrial fibrillation: Both heart rate-increasing and heart rate-decreasing variants at this locus are associated with altered atrial fibrillation risk.
Evidence quality The primary evidence comes from a large two-stage GWAS meta-analysis of up to 181,171 individuals, predominantly of European ancestry, with additional contributions from participants of Indian Asian ancestry. The GJA1-adjacent locus is among seven regions confirmed at genome-wide significance (P < 5 x 10^-8), and this locus was already established in earlier GWAS work before being confirmed in this larger analysis, providing a degree of independent replication. The seven established loci together explain only about 0.7% of resting heart rate variance, consistent with individually modest effects typical of common genetic variants. Associations with cardiac conduction, sick sinus syndrome, and atrial fibrillation derive from genetic susceptibility analyses within the same study population, which limits fully independent replication of these secondary associations. No conflicting findings are reported within the provided evidence.
Tissue-specific expression effects The following eQTL (expression quantitative trait locus - a variant associated with different levels of nearby gene activity in specific tissues) associations reflect possible molecular mechanisms, not direct clinical outcomes.
- GJA1: This variant is associated with increased GJA1 expression in tibial nerve tissue. GTEx Portal
- ENSG00000289871: This variant is associated with increased expression in non-sun-exposed (suprapubic) skin and subcutaneous adipose tissue, and with decreased expression in aortic artery tissue. GTEx Portal
- ENSG00000301655: This variant is associated with decreased expression in testis tissue. GTEx Portal
Lifestyle considerations No lifestyle considerations on file for this variant.
Frequently asked questions
What is rs1015451 and where is it located?
rs1015451 is a common single-nucleotide variant (a single DNA letter change) located near GJA1 and flanked by the pseudogenes RPL23AP48 and HMGB3P18. It was confirmed as one of seven established genetic loci for resting heart rate in a large genome-wide study of up to 181,171 people.
Is rs1015451 linked to heart disease?
Research links rs1015451 and nearby variants to resting heart rate, altered cardiac conduction, and changed risk of atrial fibrillation and sick sinus syndrome. These are statistical associations from large population studies, not diagnoses or direct measures of individual disease risk.
How large was the study that identified this variant?
The key study used a two-stage genome-wide meta-analysis of up to 181,171 individuals, predominantly of European ancestry with additional Indian Asian ancestry participants, making it one of the largest heart rate genetics studies at the time.
What is sick sinus syndrome?
Sick sinus syndrome is a group of heart rhythm problems caused by dysfunction of the heart's natural pacemaker region (the sinus node), leading to heartbeats that are too slow, too fast, or irregular. Genetic variants that increase heart rate at this locus are associated with lower risk of this condition.
What tissues does rs1015451 affect gene expression in?
GTEx data show that rs1015451 is associated with increased GJA1 gene activity in tibial nerve tissue, increased expression of another nearby gene in non-sun-exposed skin and subcutaneous fat, and decreased expression in aortic artery and testis tissue. These are expression-level associations that may reflect biological mechanisms, not direct clinical outcomes.