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Title | Identification of genetic heterogeneity of Alzheimer's disease across age |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Lo M-T, Kauppi K, Fan C-C, Sanyal N, Reas ET, Sundar VS, Lee W-C, Desikan RS, McEvoy LK, Chen C-H |
Corporate Authors | Alzheimer's Disease Genetics Consortium |
Journal | Neurobiol Aging |
Volume | 84 |
Pagination | 243.e1-243.e9 |
Date Published | 12/2019 |
ISSN | 1558-1497 |
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. |
DOI | 10.1016/j.neurobiolaging.2019.02.022 |
Alternate Journal | Neurobiol. Aging |
PubMed ID | 30979435 |
PubMed Central ID | PMC6783343 |
Grant List | R01 MH100351 / MH / NIMH NIH HHS / United States R56 AG061163 / AG / NIA NIH HHS / United States U01 AG032984 / AG / NIA NIH HHS / United States |