Lo, Min-TzuMin-TzuLoKauppi, KarolinaKarolinaKauppiFan, Chun-ChiehChun-ChiehFanSanyal, NilotpalNilotpalSanyalReas, Emilie TEmilie TReasSundar, V SV SSundarWEN-CHUNG LEEDesikan, Rahul SRahul SDesikanMcEvoy, Linda KLinda KMcEvoyChen, Chi-HuaChi-HuaChen2019-07-052019-07-052019-03-1201974580https://scholars.lib.ntu.edu.tw/handle/123456789/412786The 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 (rg = 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 × 10-6) 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.enAlzheimer's disease; Gene-based analysis; Genetic correlation; Genetic heterogeneity; Stratified GWAS[SDGs]SDG3apolipoprotein E; BIN1 protein; brain protein; MS4A4E protein; OR2S2 protein; PICALM protein; unclassified drug; adult; age; age distribution; aged; Alzheimer disease; Article; chromosome 19; controlled study; gene; gene locus; genetic correlation; genetic heterogeneity; genetic variation; genome-wide association study; human; major clinical study; onset age; OR2S2 gene; priority journal; single nucleotide polymorphism; Alzheimer disease; genetics; Alzheimer Disease; Genetic Heterogeneity; Humansjournal article10.1016/j.neurobiolaging.2019.02.022309794352-s2.0-85064014761https://api.elsevier.com/content/abstract/scopus_id/85064014761