rs12253763 (TMEM273): Atrial Fibrillation Risk Locus

Key takeaways

• rs12253763 sits near TMEM273 and C10orf71-AS1 on chromosome 10, two genes with uncharacterized roles in heart rhythm
• Large genome-wide meta-analyses of more than 250,000 atrial fibrillation cases identified this locus among hundreds of significant genetic signals
• Atrial fibrillation is the most common heart rhythm disorder worldwide and a leading cause of stroke and heart failure
• In testis tissue, the effect allele is linked to increased expression of the nearby FAM170B gene, but no heart-tissue expression effect is on record
• No variant-specific effect size has been reported for this locus in the studies available

What the research says A meta-analysis of genome-wide association studies spanning more than 180,000 atrial fibrillation (AF) cases identified over 350 AF-associated loci, with candidate genes at 139 of those loci relating to muscle contractility, cardiac muscle development, and cell-cell communication. A cross-population meta-analysis of 252,438 AF cases extended the catalogue to 525 genome-wide significant loci, estimated that common variants explain approximately 11.2% (95% CI: 9.2-13.2%) of AF liability variance in European-ancestry samples, and confirmed consistent effect estimates between discovery and replication datasets at 479 of 493 European loci. The rs12253763 locus near TMEM273 (transmembrane protein 273) and C10orf71-AS1 (a long non-coding RNA; together referred to below as this locus) was identified within these large-scale discovery efforts.

Reported associations

• Atrial fibrillation: This locus was reported as one of more than 350 genome-wide significant AF loci in a meta-analysis of over 180,000 cases; candidate genes across the full set of loci were linked to cardiac muscle development, muscle contractility, and cell-cell communication
• Atrial fibrillation (cross-population): A cross-population meta-analysis of 252,438 AF cases identified 525 genome-wide significant loci; common variants explain approximately 11.2% (95% CI: 9.2-13.2%) of AF liability variance in European populations under a 2% disease prevalence assumption

Evidence quality Both meta-analyses are large-scale collaborative efforts with strong statistical power: the first exceeding 180,000 AF cases and the second exceeding 252,000 cases spanning European, East Asian, African, and Admixed American populations. Within the European meta-analysis, 479 of 493 loci showed consistent effect estimates between discovery and replication datasets, and only five showed significant heterogeneity across contributing studies, indicating overall methodological robustness. However, no variant-specific odds ratio, beta coefficient, or confidence interval for rs12253763 is provided in the reviewed study text, making it impossible to quantify the association magnitude at this individual locus. The available evidence is consistent with a genuine population-level association signal, but locus-specific functional validation has not been described and the single-variant evidence should be considered preliminary.

Tissue-specific expression effects

• FAM170B: This gene, located near this locus, shows increased expression in testis tissue when the effect allele is present; no cardiac or atrial expression effects for FAM170B, TMEM273, or C10orf71-AS1 are reported in the available data GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.