Premium
Heterogeneous polygenic predisposition to Alzheimer’s disease in the Apolipoprotein E region
Author(s) -
Kulminski Alexander M.,
Philipp Ian,
Loika Yury,
He Liang
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.038164
Subject(s) - single nucleotide polymorphism , apolipoprotein e , genetics , linkage disequilibrium , allele , biology , genetic association , genotype , disease , gene , medicine
Background Despite recent advances, the role of genetic variants in the ApoE region in Alzheimer’s disease (AD), including ApoE4 and ApoE2 alleles, is still controversial. For example, although most researchers believe that the strongest adverse genetic association between the ApoE4 allele and AD is due to this allele itself, others argue that this link is mediated by variants from non‐ ApoE genes in this region. A role of the potentially beneficial ApoE2 allele in AD is even more controversial. Method We used the standardized third mixed moment (coskewness) metric, which generalizes linkage disequilibrium (LD) between pairs of single nucleotide polymorphisms (SNPs), to gain insights into a more homogeneous polygenic architecture of AD in the ApoE region. We examined coskewness using genotypes of 32 SNPs representing BCAM‐NECTIN2‐TOMM40‐ApoE‐ApoC1 region in a mega sample of 2,799 AD‐affected and 16,354 unaffected Caucasians from four independent studies. Associations of triples of SNPs with AD were assessed by contrasting the differences in coskewness between AD‐affected and unaffected subjects. We emphasized coskewness for triples harboring ApoE2 (rs7412) and/or ApoE4 (rs429358) coding SNPs. Result For 32 SNPs, there were 4,960 triples. The analysis of the mega sample of four studies combined identified 306 triples of SNPs from all five genes associated with AD at Bonferroni‐adjusted significance level ( p < 10 −5 = 0.05/4960). Of them, 275 triples (90%) were validated by examining consistency of directions of the associations in two subsets of independent studies comprising this mega sample that is widely regarded as replication. Of these 275 validated triples, 43 triples included rs429358 and 17 triples included rs7412. In addition, three triples included both these SNPs and SNPs from TOMM40 (rs2075650), ApoE (rs405509), and ApoC1 (rs12721046) genes. For a vast majority of validated triples, the associations with AD were not explained by pairwise LD between SNPs. Conclusion These results indicate AD‐associated structuring genetic processes in Caucasians. They provide compelling support for heterogeneous polygenic predisposition to AD in the ApoE region in the form of compound genotypes and haplotypes. They suggest coherent, rather than independent, role of the ApoE2 (rs7412) and ApoE4 (rs429358) coding SNPs and other SNPs in the ApoE region in AD.