Genetic and regulatory architecture of Alzheimer's disease in the APOE region

Abstract

Introduction Apolipoprotein E (APOE) ε2 and ε4 alleles encoded by rs7412 and rs429358 polymorphisms, respectively, are landmark contra and pro “risk” factors for Alzheimer's disease (AD). Methods We examined differences in linkage disequilibrium (LD) structures between (1) AD‐affected and unaffected subjects and (2) older AD‐unaffected and younger subjects in the 19q13.3 region harboring rs7412 and rs429358. Results AD is associated with sex‐nonspecific heterogeneous patterns of decreased and increased LD of rs7412 and rs429358, respectively, with other polymorphisms from five genes in this region in AD‐affected subjects. The LD patterns in older AD‐unaffected subjects resembled those in younger individuals. Polarization of the ε4‐ and ε2 allele–related heterogeneous LD clusters differentiated cell types and implicated specific tissues in AD pathogenesis. Discussion Protection and predisposition to AD is characterized by an interplay of rs7412 and rs429358, with multiple polymorphisms in the 19q13.3 region in a tissue‐specific manner, which is not driven by common evolutionary forces.

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

“…Our results raise a fundamental issue of a driving force of AD‐related haplotypes. By contrasting pairwise LD in younger and older subjects, we recently showed that LD structures observed in older AD‐free subjects and the younger subjects who were not under noticeable mortality risk were the same 25 . This finding favors the role of recent and specific (eg, within families or communities, a divergence of ancestral groups) selection, which can be indirectly relevant to AD.…”

“…This is important in the framework of polygenic predisposition to complex diseases, as such haplotypes represent more accurate polygenic disease profiles. The complexity of the co‐skewness pattern in the APOE region is unlikely caused by pairwise LD between SNPs comprising different triples, as these SNPs have been selected not to be in strong LD 25 . This complexity supports genetic heterogeneity in susceptibility to AD beyond that related to race/ethnic differences 26 .…”

“…This 3.7‐fold difference is driven mainly by the sensitivity of the haplotype‐based method to the deviation from HWE, as haplotypes are inferred under HWE, whereas the genotype‐based metric () does not require HWE. Because HWE for individual SNPs in full samples of LOADFS and non‐LOADFS (Table S1) does not guarantee HWE for subsamples (eg, as those stratified by the AD status) or at haplotype level (see Methods), consistently with the case of LD between SNP pairs, 20,21,25 the deviation from HWE is likely meaningful. This means that such a departure is unlikely an artifact but rather the result of some unobserved biological processes in an organism.…”

“…Then we used the mega sample of all studies combined to increase statistical power. This study did not examine the roles of sex and age as we showed their trivial effect for the same SNPs 25 …”

“…Some studies attempted to access the differences in LD structures in the APOE region between AD‐affected and unaffected subjects qualitatively 22,23 . Recently we reported significant associations of both the entire SNP patterns and specific SNPs pairs in the APOE region with AD in populations of different ancestries 24–26 …”