Genetic Variation in Genes Underlying Diverse Dementias May Explain a Small Proportion of Cases in the Alzheimer's Disease Sequencing Project.

TitleGenetic Variation in Genes Underlying Diverse Dementias May Explain a Small Proportion of Cases in the Alzheimer's Disease Sequencing Project.
Publication TypeJournal Article
Year of Publication2018
AuthorsBlue EE, Bis JC, Dorschner MO, Tsuang DW, Barral SM, Beecham G, Below JE, Bush WS, Butkiewicz M, Cruchaga C, DeStefano A, Farrer LA, Goate A, Haines J, Jaworski J, Jun G, Kunkle B, Kuzma A, Lee JJ, Lunetta KL, Ma Y, Martin E, Naj A, Nato AQ, Navas P, Nguyen H, Reitz C, Reyes D, Salerno W, Schellenberg GD, Seshadri S, Sohi H, Thornton TA, Valadares O, van Duijn C, Vardarajan BN, San Wang L-, Boerwinkle E, Dupuis J, Pericak-Vance MA, Mayeux R, Wijsman EM
Corporate Authorson behalf of the Alzheimer’s Disease Sequencing Project
JournalDement Geriatr Cogn Disord
Volume45
Issue1-2
Pagination1-17
Date Published2018
ISSN1421-9824
KeywordsAged, Aged, 80 and over, Alzheimer Disease, Case-Control Studies, Cohort Studies, Dementia, Female, Genetic Variation, Genome-Wide Association Study, Humans, Male, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Prevalence, Sequence Analysis, DNA
Abstract

BACKGROUND/AIMS: The Alzheimer's Disease Sequencing Project (ADSP) aims to identify novel genes influencing Alzheimer's disease (AD). Variants within genes known to cause dementias other than AD have previously been associated with AD risk. We describe evidence of co-segregation and associations between variants in dementia genes and clinically diagnosed AD within the ADSP.

METHODS: We summarize the properties of known pathogenic variants within dementia genes, describe the co-segregation of variants annotated as "pathogenic" in ClinVar and new candidates observed in ADSP families, and test for associations between rare variants in dementia genes in the ADSP case-control study. The participants were clinically evaluated for AD, and they represent European, Caribbean Hispanic, and isolate Dutch populations.

RESULTS/CONCLUSIONS: Pathogenic variants in dementia genes were predominantly rare and conserved coding changes. Pathogenic variants within ARSA, CSF1R, and GRN were observed, and candidate variants in GRN and CHMP2B were nominated in ADSP families. An independent case-control study provided evidence of an association between variants in TREM2, APOE, ARSA, CSF1R, PSEN1, and MAPT and risk of AD. Variants in genes which cause dementing disorders may influence the clinical diagnosis of AD in a small proportion of cases within the ADSP.

DOI10.1159/000485503
Alternate JournalDement Geriatr Cogn Disord
PubMed ID29486463
PubMed Central IDPMC5971141
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