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

ABSTRACT: Introduction:Apolipoprotein E (APOE) ?2 and ?4 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 ?4- and ?2 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.

SUBMITTER: Kulminski AM 

PROVIDER: S-EPMC7085286 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature