Linkage analyses in Caribbean Hispanic families identify novel loci associated with familial late-onset Alzheimer's disease

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• 作者：Sandra Barral^a ; ^b ; ^c ; Rong Cheng^a ; ^b ; Christiane Reitz^a ; ^b ; ^c ; ^d ; Badri Vardarajan^a ; ^b ; ^c ; Joseph Lee^a ; ^b ; ^d ; Brian Kunkle^f ; Gary Beecham^f ; Laura S. Cantwell^g ; Margaret A. Pericak-Vance^f ; ^h ; Lindsay A. Farrerⁱ ; ^j ; ^k ; ^l ; ^m ; Jonathan L. Hainesⁿ ; Alison M. Goate^o ; Tatiana Foroud^p ; Eric Boerwinkle^e ; ^q ; Gerard D. Schellenberg^g ; Richard Mayeux^a ; ^b ; ^c ; ^d ; ^{rpm2@cumc.columbia.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Caribbean Hispanic families ; Late-onset Alzheimer's disease ; Linkage analysis ; Joint linkage and association
• 刊名：Alzheimer's & Dementia
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：11
• 期：12
• 页码：1397-1406
• 全文大小：1094 K

文摘

We performed linkage analyses in Caribbean Hispanic families with multiple late-onset Alzheimer's disease (LOAD) cases to identify regions that may contain disease causative variants.

Methods

We selected 67 LOAD families to perform genome-wide linkage scan. Analysis of the linked regions was repeated using the entire sample of 282 families. Validated chromosomal regions were analyzed using joint linkage and association.

Results

We identified 26 regions linked to LOAD (HLOD ≥3.6). We validated 13 of the regions (HLOD ≥2.5) using the entire family sample. The strongest signal was at 11q12.3 (rs2232932: HLOD_max = 4.7, P_joint = 6.6 × 10⁻⁶), a locus located ∼2 Mb upstream of the membrane-spanning 4A gene cluster. We additionally identified a locus at 7p14.3 (rs10255835: HLOD_max = 4.9, P_joint = 1.2 × 10⁻⁵), a region harboring genes associated with the nervous system (GARS, GHRHR, and NEUROD6).

Discussion

Future sequencing efforts should focus on these regions because they may harbor familial LOAD causative mutations.