Identification of genetic heterogeneity of Alzheimer's disease across age

TitleIdentification of genetic heterogeneity of Alzheimer's disease across age
Publication TypeJournal Article
Year of Publication2019
AuthorsLo M-T, Kauppi K, Fan C-C, Sanyal N, Reas ET, Sundar VS, Lee W-C, Desikan RS, McEvoy LK, Chen C-H
Corporate AuthorsAlzheimer's Disease Genetics Consortium
JournalNeurobiol Aging
Date Published12/2019

The risk of APOE for Alzheimer's disease (AD) is modified by age. Beyond APOE, the polygenic architecture may also be heterogeneous across age. We aim to investigate age-related genetic heterogeneity of AD and identify genomic loci with differential effects across age. Stratified gene-based genome-wide association studies and polygenic variation analyses were performed in the younger (60-79 years, N = 14,895) and older (≥80 years, N = 6559) age-at-onset groups using Alzheimer's Disease Genetics Consortium data. We showed a moderate genetic correlation (r = 0.64) between the two age groups, supporting genetic heterogeneity. Heritability explained by variants on chromosome 19 (harboring APOE) was significantly larger in younger than in older onset group (p < 0.05). APOE region, BIN1, OR2S2, MS4A4E, and PICALM were identified at the gene-based genome-wide significance (p < 2.73 × 10) with larger effects at younger age (except MS4A4E). For the novel gene OR2S2, we further performed leave-one-out analyses, which showed consistent effects across subsamples. Our results suggest using genetically more homogeneous individuals may help detect additional susceptible loci.

Alternate JournalNeurobiol. Aging
PubMed ID30979435
PubMed Central IDPMC6783343
Grant ListR01 MH100351 / MH / NIMH NIH HHS / United States
R56 AG061163 / AG / NIA NIH HHS / United States
U01 AG032984 / AG / NIA NIH HHS / United States