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

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

Author information

1
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY, USA; Gertrude H. Sergievsky Center, Columbia University Medical Center, New York, NY, USA; Department of Neurology, Columbia University Medical Center and New York Presbyterian Hospital, New York, NY, USA.
2
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY, USA; Gertrude H. Sergievsky Center, Columbia University Medical Center, New York, NY, USA.
3
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY, USA; Gertrude H. Sergievsky Center, Columbia University Medical Center, New York, NY, USA; Department of Neurology, Columbia University Medical Center and New York Presbyterian Hospital, New York, NY, USA; Department of Epidemiology, School of Public Health, Columbia University, New York, NY, USA.
4
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY, USA; Gertrude H. Sergievsky Center, Columbia University Medical Center, New York, NY, USA; Department of Epidemiology, School of Public Health, Columbia University, New York, NY, USA.
5
The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA.
6
Perelman School of Medicine University of Pennsylvania, Philadelphia, PA, USA.
7
The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA; Dr. John T. Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL, USA.
8
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA; Department of Medicine (Biomedical Genetics), Boston University School of Medicine and Public Health, Boston, MA, USA; Department of Neurology, Boston University School of Medicine and Public Health, Boston, MA, USA; Department of Ophthalmology, Boston University School of Medicine and Public Health, Boston, MA, USA; Department of Epidemiology, Boston University School of Medicine and Public Health, Boston, MA, USA.
9
Department of Epidemiology & Biostatistics, Case Western Reserve University, Cleveland, OH, USA.
10
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
11
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
12
Department of Epidemiology, Human Genetics, and Environmental Sciences (EHGES), University of Texas School of Public Health at Houston, Houston, TX, USA; Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA.
13
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY, USA; Gertrude H. Sergievsky Center, Columbia University Medical Center, New York, NY, USA; Department of Neurology, Columbia University Medical Center and New York Presbyterian Hospital, New York, NY, USA; Department of Epidemiology, School of Public Health, Columbia University, New York, NY, USA. Electronic address: rpm2@cumc.columbia.edu.

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.

KEYWORDS:

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

PMID:
26433351
PMCID:
PMC4690771
DOI:
10.1016/j.jalz.2015.07.487
[Indexed for MEDLINE]
Free PMC Article

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