Haplotype architecture of the Alzheimer's risk in the APOE region via co‐skewness

INTRODUCTION: As a multifactorial polygenic disorder, Alzheimer's disease (AD) can be associated with complex haplotypes or compound genotypes. METHODS: We examined associations of 4960 single nucleotide polymorphism (SNP) triples, comprising 32 SNPs from five genes in the apolipoprotein E gene (APOE) region with AD in a sample of 2789 AD‐affected and 16,334 unaffected subjects. RESULTS: We identified a large number of 1127 AD‐associated triples, comprising SNPs from all five genes, in support of definitive roles of complex haplotypes in predisposition to AD. These haplotypes may not include the APOE ε4 and ε2 alleles. For triples with rs429358 or rs7412, which encode these alleles, AD is characterized mainly by strengthening connections of the ε4 allele and weakening connections of the ε2 allele with the other alleles in this region. DISCUSSION: Dissecting heterogeneity attributed to AD‐associated complex haplotypes in the APOE region will target more homogeneous polygenic profiles of people at high risk of AD.