APOE and sex‐stratified genome‐wide meta‐analyses of Alzheimer’s disease

Abstract

AbstractBackgroundGenome‐wide studies have identified diverse susceptibility genes for Alzheimer’s disease, with the APOE locus being the major risk factor known so far. However, pathogenic mechanisms and the influence of other known AD loci or patient characteristics such as gender have been poorly explored. The ADAPTED IMI consortium, focused on exploring the APOE biology, has conducted the first genome‐wide meta‐analysis of AD stratified according to the three main APOE haplotypes. Additionally, we also explored the effect of gender on AD by performing sex‐stratified meta‐analysis.MethodsAPOE stratified meta‐analysis was performed in three stages comprising 39,186 human samples from sixteen datasets including ADNI, AddNeuroMed, ADGC, Mayo, Neocodex‐Murcia, NIA, ROSMAP, TGEN study for Stage I, GR@ACE and GERAD for Stage II and ARIC, CHS, FHS and RS (CHARGE consortium) for Stage III. Sex‐stratified meta‐analysis was performed on Stage I and Stage II datasets.After quality control and imputation, association of genotype dosages with the AD case‐control status for each dataset was investigated through regression models adjusted by age, sex and the first four PC vectors, plus APOE status in the sex stratified analysis. Meta‐analysis was performed using the inverse variance weighing method. Results were summarized on gene‐level and explored for enrichment in known pathways and processes.ResultsIn the combined analysis, we identified genome‐wide significant signals for APOE, BIN1, CLU, PICALM and a large intergenic region in 4p15 in the APOE ε4 stratum, and for ABCA7, BIN1 and PICALM in the APOE ε3 stratum, whereas no genome‐wide significant results were found in the APOE ε2 stratum. Sex‐stratified analysis identified genome‐wide significant signals for BIN1 and APOE as well as suggestive signals for PICALM, MYLK, SOX5 and SCEL in the female stratum. By contrast in males, only suggestive signals for BIN1, APOE, ZCCHC2, the ABI3BP/IMPG2 locus, ESRRB and the 19q13.4 leukocyte receptor cluster were identified. Accordingly, APOE‐ and sex‐specific pathways were highlighted.ConclusionsThis systematic stratified analysis led to the identification of loci associated with AD risk, which are specific for certain APOE haplotypes and specific combinations of APOE haplotypes and gender. This novel insight contributes to unravel the complex architecture of AD pathology.