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

Sandra Barral, Rong Cheng, Christiane Reitz, Badri Vardarajan, Joseph Lee, Brian Kunkle, Gary W Beecham, Laura S. Cantwell, Margaret A Pericak-Vance, Lindsay A. Farrer, Jonathan L. Haines, Alison M. Goate, Tatiana Foroud, Eric Boerwinkle, Gerard D. Schellenberg, Richard Mayeux

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Introduction 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: HLODmax = 4.7, Pjoint = 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: HLODmax = 4.9, Pjoint = 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.

Original languageEnglish (US)
Pages (from-to)1397-1406
Number of pages10
JournalAlzheimer's and Dementia
Volume11
Issue number12
DOIs
StatePublished - Dec 1 2015

Fingerprint

Hispanic Americans
Alzheimer Disease
Multigene Family
Nervous System
Joints
Genome
Mutation
Membranes
Alzheimer disease type 2
Genes

Keywords

  • Caribbean Hispanic families
  • Joint linkage and association
  • Late-onset Alzheimer's disease
  • Linkage analysis

ASJC Scopus subject areas

  • Clinical Neurology
  • Developmental Neuroscience
  • Cellular and Molecular Neuroscience
  • Psychiatry and Mental health
  • Geriatrics and Gerontology
  • Epidemiology
  • Health Policy

Cite this

Linkage analyses in Caribbean Hispanic families identify novel loci associated with familial late-onset Alzheimer's disease. / Barral, Sandra; Cheng, Rong; Reitz, Christiane; Vardarajan, Badri; Lee, Joseph; Kunkle, Brian; Beecham, Gary W; Cantwell, Laura S.; Pericak-Vance, Margaret A; Farrer, Lindsay A.; Haines, Jonathan L.; Goate, Alison M.; Foroud, Tatiana; Boerwinkle, Eric; Schellenberg, Gerard D.; Mayeux, Richard.

In: Alzheimer's and Dementia, Vol. 11, No. 12, 01.12.2015, p. 1397-1406.

Research output: Contribution to journalArticle

Barral, S, Cheng, R, Reitz, C, Vardarajan, B, Lee, J, Kunkle, B, Beecham, GW, Cantwell, LS, Pericak-Vance, MA, Farrer, LA, Haines, JL, Goate, AM, Foroud, T, Boerwinkle, E, Schellenberg, GD & Mayeux, R 2015, 'Linkage analyses in Caribbean Hispanic families identify novel loci associated with familial late-onset Alzheimer's disease', Alzheimer's and Dementia, vol. 11, no. 12, pp. 1397-1406. https://doi.org/10.1016/j.jalz.2015.07.487
Barral, Sandra ; Cheng, Rong ; Reitz, Christiane ; Vardarajan, Badri ; Lee, Joseph ; Kunkle, Brian ; Beecham, Gary W ; Cantwell, Laura S. ; Pericak-Vance, Margaret A ; Farrer, Lindsay A. ; Haines, Jonathan L. ; Goate, Alison M. ; Foroud, Tatiana ; Boerwinkle, Eric ; Schellenberg, Gerard D. ; Mayeux, Richard. / Linkage analyses in Caribbean Hispanic families identify novel loci associated with familial late-onset Alzheimer's disease. In: Alzheimer's and Dementia. 2015 ; Vol. 11, No. 12. pp. 1397-1406.
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AU - Cheng, Rong

AU - Reitz, Christiane

AU - Vardarajan, Badri

AU - Lee, Joseph

AU - Kunkle, Brian

AU - Beecham, Gary W

AU - Cantwell, Laura S.

AU - Pericak-Vance, Margaret A

AU - Farrer, Lindsay A.

AU - Haines, Jonathan L.

AU - Goate, Alison M.

AU - Foroud, Tatiana

AU - Boerwinkle, Eric

AU - Schellenberg, Gerard D.

AU - Mayeux, Richard

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N2 - Introduction 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: HLODmax = 4.7, Pjoint = 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: HLODmax = 4.9, Pjoint = 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.

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