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

doi:10.1016/j.jalz.2015.07.487

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.

Authors

Sandra Barral¹, Rong Cheng², Christiane Reitz³, Badri Vardarajan¹, Joseph Lee⁴, Brian Kunkle⁵, Gary Beecham⁵, Laura S Cantwell⁶, Margaret A Pericak-Vance⁷, Lindsay A Farrer⁸, Jonathan L Haines⁹, Alison M Goate¹⁰, Tatiana Foroud¹¹, Eric Boerwinkle¹², Gerard D Schellenberg⁶, Richard Mayeux¹³

Affiliations

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.

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

Abstract

Publication types

MeSH terms

Grants and funding