Genome-wide linkage analyses of non-Hispanic white families identify novel loci for familial late-onset Alzheimer's disease

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• 作者：Brian W. Kunkle^a ; James Jaworski^a ; Sandra Barral^b ; ^c ; ^d ; Badri Vardarajan^b ; ^c ; ^f ; ^g ; Gary W. Beecham^a ; Eden R. Martin^a ; Laura S. Cantwell^h ; Amanda Partch^h ; Thomas D. Birdⁱ ; ^j ; Wendy H. Raskind^j ; ^k ; Anita L. DeStefano^l ; Regina M. Carney^a ; ^m ; Michael Cuccaro^a ; ⁿ ; Jeffrey M. Vance^a ; ⁿ ; Lindsay A. Farrer^k ; ^o ; ^p ; ^q ; ^r ; Alison M. Goate^f ; ^g ; Tatiana Foroud^s ; Richard P. Mayeux^b ; ^c ; ^d ; ^e ; ^t ; Gerard D. Schellenberg^h ; Jonathan L. Haines^u ; Margaret A. Pericak-Vance^a ; ⁿ ; ^{mpericak@med.miami.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Non-Hispanic white ; Late-onset Alzheimer's disease ; Linkage ; High penetrance ; Identity by descent ; Familial ; Genetics
• 刊名：Alzheimer's & Dementia
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：12
• 期：1
• 页码：2-10
• 全文大小：901 K

文摘

Few high penetrance variants that explain risk in late-onset Alzheimer's disease (LOAD) families have been found.

Methods

We performed genome-wide linkage and identity-by-descent (IBD) analyses on 41 non-Hispanic white families exhibiting likely dominant inheritance of LOAD, and having no mutations at known familial Alzheimer's disease (AD) loci, and a low burden of APOE ε4 alleles.

Results

Two-point parametric linkage analysis identified 14 significantly linked regions, including three novel linkage regions for LOAD (5q32, 11q12.2–11q14.1, and 14q13.3), one of which replicates a genome-wide association LOAD locus, the MS4A6A-MS4A4E gene cluster at 11q12.2. Five of the 14 regions (3q25.31, 4q34.1, 8q22.3, 11q12.2–14.1, and 19q13.41) are supported by strong multipoint results (logarithm of odds [LOD*] ≥1.5). Nonparametric multipoint analyses produced an additional significant locus at 14q32.2 (LOD* = 4.18). The 1-LOD confidence interval for this region contains one gene, C14orf177, and the microRNA Mir_320, whereas IBD analyses implicates an additional gene BCL11B, a regulator of brain-derived neurotrophic signaling, a pathway associated with pathogenesis of several neurodegenerative diseases.

Discussion

Examination of these regions after whole-genome sequencing may identify highly penetrant variants for familial LOAD.