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Identification of genetic heterogeneity of Alzheimer's disease across age
Umeå University, Faculty of Medicine, Department of Radiation Sciences. Center for Multimodal Imaging and Genetics, Department of Radiology, University of California, San Diego, CA, USA.ORCID iD: 0000-0003-4908-341X
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2019 (English)In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 84, p. 243.e1-243.e9Article in journal (Refereed) Published
Abstract [en]

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(g) = 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 x 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. Published by Elsevier Inc.

Place, publisher, year, edition, pages
Elsevier, 2019. Vol. 84, p. 243.e1-243.e9
Keywords [en]
Alzheimer's disease, Genetic heterogeneity, Genetic correlation, Stratified GWAS, Gene-based analysis
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
URN: urn:nbn:se:umu:diva-167246DOI: 10.1016/j.neurobiolaging.2019.02.022ISI: 000501576800050PubMedID: 30979435Scopus ID: 2-s2.0-85064014761OAI: oai:DiVA.org:umu-167246DiVA, id: diva2:1385298
Funder
Swedish Research Council, 2217-03011Available from: 2020-01-14 Created: 2020-01-14 Last updated: 2020-01-14Bibliographically approved

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Kauppi, Karolina

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