<i>APOE‐</i>ε4 interacts with the <i>BTBD7</i> testis‐eQTL to reduce longevity in males

Abstract Background The ε4 allele of the APOE gene ( APOE ‐ε4) and male sex are well‐established risk factors for reduced longevity. While many genetic studies of longevity have modeled sex and APOE , independently, few have considered the interaction of these two risk factors. Here, we model the interaction between APOE‐ε 4 and sex in a genome‐wide association study (GWAS) of longevity. Method This study included a total of 408,780 participants with 36,981 age‐at‐death (male = 21,912, female = 15,069) and 371,799 last‐known‐age (male = 165,849, female = 205,950) from European ancestry participants in UK Biobank ( Table 1 ). We performed a GWAS stratified by sex to find significant variant APOE‐ε 4 genotype interactions associated with longevity using imputed genotype data for common variants (allele frequency&gt;1%). Additionally, we conducted colocalization analyses with expression quantitative loci (eQTL) in GTEx v8 to identify potentially causal genes. Result In males ( p = 4.1×10 −8 ), but not in females ( p = 0.33), we found a significant interaction between APOE‐ε 4 and rs11626499 near BTBD7 , which was associated with decreased longevity ( Figure 1 ). The survival analysis revealed that in the male APOE‐ε 4 carrier group, the individuals with the rs11626499_G had a higher risk of mortality ( p = 2.8×10 −7 , HR = 1.12), but this risk was not observed in the male APOE‐ε 4 non‐carrier group ( p = 0.06) or in the female APOE‐ε 4 carrier group ( p = 0.14). Furthermore, the GWAS signal colocalizes with associations of BTBD7 and UNC79 expression in testis ( Figure 2 ). Conclusion We identified an interaction between APOE‐ε 4 and rs11626499 that increases mortality risk only in males. Additionally, rs11626499_G is associated with decreased BTBD7 and increased UNC79 expression in testis but not in female‐specific tissues. These findings demonstrate the importance of modeling the interaction between APOE and sex in studies of longevity.