Inter- and intra-chromosomal modulators of the APOE ϵ2 and ϵ4 effects on the Alzheimer's disease risk

Abstract

The mechanisms of incomplete penetrance of risk modifying impacts of apolipoprotein E (APOE) {varepsilon}2 and {varepsilon}4 alleles on Alzheimers disease (AD) have not been fully understood. We performed genome-wide analysis of differences in linkage disequilibrium (LD) patterns between 6136 AD-affected and 10555 AD-unaffected subjects from five independent studies to explore whether the association of the APOE {varepsilon}2 allele (encoded by rs7412 polymorphism) and {varepsilon}4 allele (encoded by rs429358 polymorphism) with AD was modulated by autosomal polymorphisms. The LD analysis identified 24 (mostly inter-chromosomal) and 57 (primarily intra-chromosomal) autosomal polymorphisms with significant differences in LD with either rs7412 or rs429358, respectively, between AD-affected and AD-unaffected subjects, indicating their potential modulatory roles. Our Cox regression analysis showed that minor alleles of four inter-chromosomal and ten intra-chromosomal polymorphisms exerted significant modulating effects on the {varepsilon}2- and {varepsilon}4-associated AD risks, respectively, and identified {varepsilon}2-independent (rs2884183 polymorphism, 11q22.3) and {varepsilon}4-independent (rs483082 polymorphism, 19q13.32) associations with AD. Our functional analysis highlighted {varepsilon}2- and/or {varepsilon}4-linked processes affecting the lipid and lipoprotein metabolism, and cell junction organization which may contribute to AD pathogenesis. These findings provide insights into the {varepsilon}2- and {varepsilon}4-associated mechanisms of AD pathogenesis, underlying their incomplete penetrance.