Sex differences in genetic susceptibility of hippocampal subfields: A polygenic association study

Background The hippocampus is involved in several complex diseases which display sex differences in their prevalence. Therefore, it can be hypothesized that sex‐specific genetic vulnerability in hippocampal formation might partially explain these differences. The aim of this study was to investigate whether the genetic predisposition to several complex diseases showed sex‐specific associations with the volumes of hippocampal subfields. Method A total of 1,071 cognitively unimpaired participants (45‐74 years) at increased risk for Alzheimer's disease (AD) (ALFA study), with available genotyping and neuroimaging data were included (62.6% women). Genetic predisposition was calculated through polygenic risk scores (PRSs) computed using the PRSice tool (v.1.25). A total of 33 PRSs were estimated from the most recent genome‐wide association meta‐analyses for several neurodegenerative, vascular and metabolic diseases, as well as for biomarkers of AD. Association analyses included the volumes of the hippocampal subfields quantified through high‐resolution 3D‐T1‐weighted magnetic resonance imaging scans and determined using Freesurfer (v.6.0). Sex‐stratified association analyses were estimated using linear regression models adjusted for age, education, and total intracranial volume. The threshold of significance was established by approximating the total number of effective tests. The resulting adjusted significance threshold was set at p