The ε4‐bearing TOMM40‐APOE‐APOC1 haplotype but not the ε4 allele confers an exceptionally high risk of Alzheimer’s disease

Abstract

The APOE gene harboring the ε2 and ε4 alleles encoded by minor alleles of rs7412 and rs429358 single nucleotide polymorphisms (SNPs), respectively, is one of the most studied genes in humans. Despite that, the problem of whether the associations between these alleles and the late-onset Alzheimer's disease (referred to as AD) are due to these alleles themselves remains controversial. This problem is complicated by an inherent heterogeneity in genetic predisposition to AD, which is common for complex diseases in late life.We used a comprehensive, two-stage strategy to gain insights into a more homogeneous genetic architecture of AD in subjects of European ancestry in the TOMM40-APOE-APOC1 region, emphasizing the role of the ε4 allele. First, we examined differences in linkage disequilibrium (LD) patterns in AD-affected and unaffected subjects who carry or do not carry the ε4 or ε2 allele to prioritize SNP pairs according to the LD differences. Second, rs429358 and SNPs from the top pair were selected to construct compound genotypes and associate them with AD. The discovery analyses used a mega-sample of 2,673 AD-affected and 16,246 cognitively normal subjects from four independent studies. The landmark Alzheimer's Disease Genetics Consortium initiative cohort (3,662 AD-cases and 1,541 controls) was used for validation.The top LD difference between the most unfavorable AD-affected ε2-free sample and the most favorable AD- and ε4-free sample was for rs2075650 (TOMM40) and rs12721046 (APOC1) SNPs, Δr=77.6% (p<10-100 ). The meta-analysis results showed the exceptionally high risk of AD for carriers of the full minor allele homozygote comprised of rs429358, rs2075650, and rs12721046 SNPs, odds ratio=18.1, p=1.96×10-77 . This risk was 4.37-fold (p=1.34×10-3 ) higher than that for carriers of two copies of the ε4 alleles who do not have minor alleles of rs2075650 and rs12721046.This study provides compelling evidence that the strongest genetic predisposition to AD in the APOE region is credited to a haplotype comprised of the ε4 allele and TOMM40 (rs2075650) and APOC1 (rs12721046) minor alleles, but not to the ε4 allele itself. This more homogeneous polygenic profile is promising for assessing subjects at an exceptionally high risk of AD.