Genome‐wide analysis identified abundant genetic modulators of contributions of the apolipoprotein E alleles to Alzheimer's disease risk

Abstract

Introduction The apolipoprotein E (APOE) ε2 and ε4 alleles have beneficial and adverse impacts on Alzheimer's disease (AD), respectively, with incomplete penetrance, which may be modulated by other genetic variants. Methods We examined whether the associations of the APOE alleles with other polymorphisms in the genome can be sensitive to AD‐affection status. Results We identified associations of the ε2 and ε4 alleles with 314 and 232 polymorphisms, respectively. Of them, 35 and 31 polymorphisms had significantly different effects in AD‐affected and ‐unaffected groups, suggesting their potential involvement in the AD pathogenesis by modulating the effects of the ε2 and ε4 alleles, respectively. Our survival‐type analysis of the AD risk supported modulating roles of multiple group‐specific polymorphisms. Our functional analysis identified gene enrichment in multiple immune‐related biological processes, for example, B cell function. Discussion These findings suggest involvement of local and inter‐chromosomal modulators of the effects of the APOE alleles on the AD risk.

Interaction Analysis Reveals Complex Genetic Associations with Alzheimer’s Disease in the CLU and ABCA7 Gene Regions

“…Our findings support previous studies implicating the roles of CLU and ABCA7 gene variants in AD [10][11][12][13][14]17,18]. As with previously reported complex genetic associations in the APOE locus, the novel CompG-AD associations identified here highlight the importance of genetic interactions in the AD risk assessment [34,36,37].…”

“…Instead, all studies report some degree of incomplete penetrance that is consistent with the complex genetic architecture of AD (e.g., haplotypes and interactions). There is a multitude of evidence of such a complex genetic landscape within the APOE 19q13.3 locus [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ]. For instance, we have shown that the linkage disequilibrium (LD) patterns in this locus are significantly different in the AD-affected subjects and AD-unaffected controls [ 30 , 31 , 32 , 37 ].…”

APOE alleles modulate associations of plasma metabolites with variants from multiple genes on chromosome 19q13.3

“…None of these group-specific SNP-metabolite associations were significant in the pooled sample of the E2, E3, and E4 groups. The group-specific associations indicate genetic heterogeneity of plasma metabolites in the APOE 19q13.3 locus, which is in line with our previous studies that demonstrated complex LD structure differentially affects AD risk in this locus ( Kulminski et al, 2018 , 2020a , b ; Nazarian et al, 2022a , b ). Therefore, we suggest APOE -stratified analyses are essential for dissecting the genetic architecture of complex diseases and traits sensitive to APOE ε2/ε3/ε4 polymorphism.…”

“…The APOE 19q13.3 locus is a genetically heterogenous region within which complex haplotype structures, interactions, and compound genotypes have been identified ( Templeton et al, 2005 ; Yu et al, 2007 ; Lescai et al, 2011 ; Lutz et al, 2016 ; Babenko et al, 2018 ; Kulminski et al, 2018 , 2020a , b , 2021 ; Zhou et al, 2019 ; Nazarian et al, 2022a , b ). For instance, linkage disequilibrium (LD) and association studies have highlighted complex genetic structure in this locus that are statistically different between AD-affected and unaffected subjects ( Kulminski et al, 2018 , 2020a , b ).…”

“…For instance, linkage disequilibrium (LD) and association studies have highlighted complex genetic structure in this locus that are statistically different between AD-affected and unaffected subjects ( Kulminski et al, 2018 , 2020a , b ). In addition, stratified analyses have identified sets of interactions and compound genotypes in the APOE locus of the ε2- and ε4-carriers, which may modify the effects of these alleles on AD risk and, to some extent, justify their incomplete penetrance ( Nazarian et al, 2022a , b ).…”