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 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 Scopus citations

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

Keywords

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

ASJC Scopus subject areas

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

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    Barral, S., Cheng, R., Reitz, C., Vardarajan, B., Lee, J., Kunkle, B., Beecham, G., Cantwell, L. S., Pericak-Vance, M. A., Farrer, L. A., Haines, J. L., Goate, A. M., Foroud, T., Boerwinkle, E., Schellenberg, G. D., & Mayeux, R. (2015). Linkage analyses in Caribbean Hispanic families identify novel loci associated with familial late-onset Alzheimer's disease. Alzheimer's and Dementia, 11(12), 1397-1406. https://doi.org/10.1016/j.jalz.2015.07.487