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
Volume84
Pagination243.e1-243.e9
Date Published12/2019
ISSN1558-1497
Abstract

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.

DOI10.1016/j.neurobiolaging.2019.02.022
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