Sex‐specific genetic predictors of memory performance

Background There are notable sex differences in the clinical manifestation of Alzheimer’s disease (AD), including differences in baseline and longitudinal changes in memory performance. However, sex‐stratified models have not been routinely incorporated into genetic studies of cognitive performance or decline. We sought to identify sex‐specific genetic predictors of memory performance in aging adults. Method We obtained harmonized memory scores from 11,601 females and 8,885 males from 7 cohorts of cognitive aging. We calculated scores using latent variable modeling techniques anchored on overlapping neuropsychological test items across datasets to perform both sex‐stratified and sex‐interaction genome‐wide association studies in each cohort using mixed‐effects regression models to assess genetic associations with baseline memory score and rate of memory decline. Covariates included age at baseline and population principal components. We then combined results in a fixed‐effect meta‐analysis. Results As expected, we observed robust associations at the APOE locus in males and females in both baseline and longitudinal models. Additionally, we identified a sex‐specific locus for longitudinal memory performance (interaction‐p=2.54e‐6) on chromosome 7 within LINC‐PINT that was genome‐wide significant in males (index SNP= rs66754621; p=1.62e‐8; MAF=0.20), but not females (p=0.65). This variant is in an enhancer region within several brain regions, as well as within a promoter‐anchored chromatin interaction loop and a methylation eQTL in the prefrontal cortex. No female‐specific loci were identified. Interestingly, we did observe nominal associations in baseline memory at some known AD loci, including male‐specific effects at MS4A6A, FERMT2, and KAT8 (interaction ps=0.0026, 0.027, and 0.0058, respectively) and opposing effects between males and females at INPP5D (interaction p=0.0021). Conclusion These results highlight a novel male‐specific locus of memory performance on chromosome 7 near the LINC‐PINT gene. LINC‐PINT is upregulated in the substantia nigra in Parkinson’s disease and is downregulated in multiple brain regions over the course of normal aging, making it a fascinating male‐specific candidate gene. Replicate and functional analyses of the region are ongoing to verify our finding and elucidate the biological mechanism. Our results add to the growing body of literature suggesting that there are sex‐specific genetic contributors to cognitive decline.