title: Disease-related mutations among Caribbean Hispanics with familial dementia.
abstract: Pathogenic mutations in the three known genes - the amyloid precursor protein (APP), presenilin 1 (PSEN1), presenilin 2 (PSEN2) - are known to cause familial Alzheimer's disease (AD) and tend to be associated with early-onset AD. However, the frequency and risk associated with these mutations vary widely. In addition, mutations in the frontotemporal lobar degeneration (FTLD) genes - the microtubule-associated protein tau (MAPT), granulin (GRN) - have also been found to be associated with clinical AD. Here, we conducted targeted resequencing of the exons in genes encoding APP, PSEN1, PSEN2, GRN, and MAPT in 183 individuals from families with four or more affected relatives, presumed to be AD, and living in the Dominican Republic and Puerto Rico. We then performed linkage and family-based association analyses in carrier families, and genotyped 498 similarly aged unrelated controls from the same ethnic background. Twelve potentially pathogenic mutations were found to be associated with disease in 53 individuals in the five genes. The most frequently observed mutation was the p.Gly206Ala variant in PSEN1 present in 30 (57%) of those sequenced. In the combined linkage and association analyses several rare variants were associated with dementia. In Caribbean Hispanics with familial AD, potentially pathogenic variants were present in 29.2%, four were novel mutations, while eight had been previously observed. In addition, some family members carried variants in the GRN and MAPT genes which are associated with FTLD.
authors.affiliation: The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University New York, New York ; The Gertrude H. Sergievsky Center, Columbia University New York, New York ; The Department of Epidemiology, School of Public Health, Columbia University New York, New York.
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Lee
authors.affiliation: The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University New York, New York.
authors.forename: Amanda
authors.initials: A
authors.lastname: Kahn
authors.affiliation: The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University New York, New York ; The Gertrude H. Sergievsky Center, Columbia University New York, New York.
authors.forename: Rong
authors.initials: R
authors.lastname: Cheng
authors.affiliation: The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University New York, New York ; The Gertrude H. Sergievsky Center, Columbia University New York, New York ; The Department of Neurology, Columbia University New York, New York.
authors.forename: Christiane
authors.initials: C
authors.lastname: Reitz
authors.affiliation: The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University New York, New York ; The Gertrude H. Sergievsky Center, Columbia University New York, New York.
authors.forename: Badri
authors.initials: B
authors.lastname: Vardarajan
authors.affiliation: The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University New York, New York ; The Department of Medicine, College of Physicians and Surgeons, Columbia University New York, New York.
authors.forename: Rafael
authors.initials: R
authors.lastname: Lantigua
authors.affiliation: School of Medicine, Pontificia Universidad Catolica Madre y Maestra Santiago, Dominican Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Medrano
authors.affiliation: Department of Internal Medicine, University of Puerto Rico School of Medicine San Juan, Puerto Rico.
authors.forename: Ivonne Z
authors.initials: IZ
authors.lastname: Jiménez-Velázquez
authors.affiliation: The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University New York, New York ; The Gertrude H. Sergievsky Center, Columbia University New York, New York ; The Department of Neurology, Columbia University New York, New York.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Williamson
authors.affiliation: The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University New York, New York ; The Department of Pathology, Columbia University New York, New York.
authors.forename: Peter
authors.initials: P
authors.lastname: Nagy
authors.affiliation: The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University New York, New York ; The Gertrude H. Sergievsky Center, Columbia University New York, New York ; The Department of Epidemiology, School of Public Health, Columbia University New York, New York ; The Department of Neurology, Columbia University New York, New York ; The Department of Psychiatry, Columbia University New York, New York.
authors.forename: Richard
authors.initials: R
authors.lastname: Mayeux
keywords: Alzheimer's disease; Caribbean Hispanics; familial dementia; mutations; next-generation sequencing