GWAS metanalysis of atrial fibrillation reveals significant sex-related heterogeneity effects of the PITX2 and CFL2 loci

Background Atrial fibrillation (AF) exhibits notable sex differences in epidemiology and outcomes. This study investigates biological sex-specific differences in AF through sex-stratified genome-wide association studies (GWAS) and proteomic related analyses. Methods We performed a sex-stratified GWAS meta-analysis using data from the UK Biobank study: 4,375 male AF cases and 162,645 controls; 1,981 female AF cases and 192,193 controls. Significant loci and sex-specific associations were identified, and sex heterogeneity was assessed. Replication was done in an independent cohort of 12,614 individuals (1,207 AF cases, 55% female). Plasma proteomic analyses in 46,724 subjects assessed genotype–sex interactions stratifying by atrial fibrillation status. Heritability estimates and sex-specific polygenic risk scores (PRS) were also calculated. Results Two male-specific loci: CFL2 and ATXN1 were identified. The meta-analysis identified additional 22 known AF loci. Sex heterogeneity was found in 6 of the 24 loci, with TTN and SPATS2L showing stronger effects in females, and NTMT2 , PITX2 , GBF1 , and CFL2 stronger effects in males. Heritability estimation liability was higher in females (h²=0.19) than in males (h²=0.12). PRS performance was similar across sexes (AUC = 0.60–0.63). Replication confirmed heterogeneity for PITX2 and CFL2 , with CFL2 variant associated with AF only in males. Proteomics analyses suggested nominals association such as: myosin light chain 1/3 (MYL1) and biogenesis of lysosomal organelles complex 1 subunit 2 (BLOC1S2). Key associated pathways included SCF-KIT signaling, prolactin signaling, and the RAC1/PAK1/p38/MMP2. Conclusions Our findings indicate significant sex-based heterogeneity in the effects of well-known AF-associated loci. Proteomic-genetic integration suggested sex-specific differences and candidate pathways. Despite this heterogeneity, a sex-specific approach did not significantly enhance PRS prediction, underscoring the need for adequately powered sex-specific GWAS.