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Rare genetic variation implicated in non-Hispanic white families with Alzheimer disease.

TitleRare genetic variation implicated in non-Hispanic white families with Alzheimer disease.
Publication TypeJournal Article
Year of Publication2018
AuthorsBeecham GW, Vardarajan B, Blue E, Bush W, Jaworski J, Barral S, DeStefano A, Hamilton-Nelson K, Kunkle B, Martin ER, Naj A, Rajabli F, Reitz C, Thornton T, van Duijn C, Goate A, Seshadri S, Farrer LA, Boerwinkle E, Schellenberg G, Haines JL, Wijsman E, Mayeux R, Pericak-Vance MA
Corporate AuthorsAlzheimer's Disease Sequencing Project
JournalNeurol Genet
Date Published2018 Dec

Objective: To identify genetic variation influencing late-onset Alzheimer disease (LOAD), we used a large data set of non-Hispanic white (NHW) extended families multiply-affected by LOAD by performing whole genome sequencing (WGS).
Methods: As part of the Alzheimer Disease Sequencing Project, WGS data were generated for 197 NHW participants from 42 families (affected individuals and unaffected, elderly relatives). A two-pronged approach was taken. First, variants were prioritized using heterogeneity logarithm of the odds (HLOD) and family-specific LOD scores as well as annotations based on function, frequency, and segregation with disease. Second, known Alzheimer disease (AD) candidate genes were assessed for rare variation using a family-based association test.
Results: We identified 41 rare, predicted-damaging variants that segregated with disease in the families that contributed to the HLOD or family-specific LOD regions. These included a variant in nitric oxide synthase 1 adaptor protein that segregates with disease in a family with 7 individuals with AD, as well as variants in , and . Rare-variant association identified 2 LOAD candidate genes associated with disease in these families: (-values = 0.001) and (-value = 0.009). These genes still showed association while controlling for common index variants, indicating the rare-variant signal is distinct from common variation that initially identified the genes as candidates.
Conclusions: We identified multiple genes with putative damaging rare variants that segregate with disease in multiplex AD families and showed that rare variation may influence AD risk at AD candidate genes. These results identify novel AD candidate genes and show a role for rare variation in LOAD etiology, even at genes previously identified by common variation.

Alternate JournalNeurol Genet
PubMed ID30569016
PubMed Central IDPMC6278241
Grant ListR01 AG054076 / AG / NIA NIH HHS / United States
U54 HG003067 / HG / NHGRI NIH HHS / United States
U01 AG049507 / AG / NIA NIH HHS / United States
U01 AG032984 / AG / NIA NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
P50 AG005136 / AG / NIA NIH HHS / United States
R01 AG033193 / AG / NIA NIH HHS / United States
U54 HG003079 / HG / NHGRI NIH HHS / United States

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