Abstract
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, β(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, β(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. HIGHLIGHTS: Our genome-wide meta-analysis of single variants identified two new genetic associations, one in males and one in females. The novel male association was observed with the decline of memory in the intergenic region near the RPS23P3 gene on chromosome 4. This intergenic region has previously been implicated in several brain and cognition related traits, including anatomical brain aging, brain shape, and educational attainment. The novel female-specific association was observed with decline in executive function on chromosome 12 near the NDUFA12 gene, which is involved in oxidative phosphorylation. Sex-stratified analyses offer sex-specific understanding of biological pathways involved in cognitive aging.