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

Alzheimers Dement. 2015 Dec;11(12):1397-1406. doi: 10.1016/j.jalz.2015.07.487. Epub 2015 Oct 1.


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.

Keywords: Caribbean Hispanic families; Joint linkage and association; Late-onset Alzheimer's disease; Linkage analysis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / genetics*
  • Chromosome Mapping / methods
  • Dominican Republic / ethnology
  • Female
  • Genetic Linkage*
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Hispanic or Latino / genetics*
  • Humans
  • Male
  • Middle Aged
  • New York City
  • Polymorphism, Single Nucleotide*
  • Puerto Rico / ethnology