Sex-stratified genome-wide meta-analysis identifies novel loci for cognitive decline in older adults

INTRODUCTION Many complex traits and diseases show sex-specific biases in clinical presentation and prevalence. METHODS To understand sex-specific genetic architecture of cognitive decline across five cognitive domains (attention, memory, executive function, language, and visuospatial function) and global cognitive function, we performed sex-stratified genome-wide meta-analysis in 3021 older adults aged >= 65 years (female = 1545, male = 1476) from three prospective cohorts. Gene-based and gene-set enrichment analyses were conducted for each cognitive trait. RESULTS We identified a novel genome-wide significant (GWS) intergenic locus for decline of memory in males near RPS23P3 on chromosome 4 (rs6851574: minor allele frequency [MAF] = 0.39, P-male = 4.10E-08, beta(male) = 0.19; P-interaction = 3.76E-04). We also identified a subthreshold GWS locus for decline of executive function on chromosome 12 in females near the NDUFA12 gene, involved in oxidative phosphorylation (rs11107823: MAF = 0.12, P-female = 9.35E-08, beta(female) = 0.28; P-interaction = 7.42E-06). DISCUSSION Sex-aware genetic studies can help in the identification of novel genetic loci and enhance sex-specific understanding of cognitive decline.