title: Age-at-onset linkage analysis in Caribbean Hispanics with familial late-onset Alzheimer's disease.
abstract: The aim of the study was to identify chromosomal regions that may harbor putative genetic variants influencing age at onset in familial late-onset Alzheimer's disease (LOAD). Data from a genome-wide scan that included genotyping of APOE were analyzed in 1,161 individuals from 209 families of Caribbean Hispanic ancestry with a mean age at onset of 73.3 years multiply affected by LOAD. Two-point and multipoint analyses were conducted using variance component methods using 376 microsatellite markers with an average intermarker distance of 9.3 cM. Family-based test of association was also conducted for the same set of markers. Age at onset of symptoms among affected individuals was used as the quantitative trait. Our results showed that the presence of APOE-epsilon4 lowered the age at onset by 3 years. Several candidate loci were identified. Using linkage analysis strategy, the highest logarithm of odds (LOD) scores were obtained using a conservative definition of LOAD at 5q15 (LOD = 3.1), 17q25.1 (LOD = 2.94), 14q32.12 (LOD = 2.36), and 7q36.3 (LOD = 2.29) in a model that adjusted for APOE-epsilon4 and other covariates. Both linkage and family-based association identified 17p13 as a candidate region. Family-based association analysis showed markers at 12q13 (p = 0.00002), 13q33 (p = 0.00043), and 14q23 (p = 0.00046) to be significantly associated with age at onset. The current study supports the hypothesis that there are additional genetic loci that could influence age at onset of late onset Alzheimer's disease. The novel loci at 5q15, 17q25.1, 13q33, and 17p13 and the previously reported loci at 7q36.3, 12q13, 14q23, and 14q32 need further investigation.
authors.affiliation: The Taub Institute on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY 10032, USA.
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Lee
authors.forename: Sandra
authors.initials: S
authors.lastname: Barral
authors.forename: Rong
authors.initials: R
authors.lastname: Cheng
authors.forename: Inara
authors.initials: I
authors.lastname: Chacon
authors.forename: Vincent
authors.initials: V
authors.lastname: Santana
authors.forename: Jennifer
authors.initials: J
authors.lastname: Williamson
authors.forename: Rafael
authors.initials: R
authors.lastname: Lantigua
authors.forename: Martin
authors.initials: M
authors.lastname: Medrano
authors.forename: Ivonne Z
authors.initials: IZ
authors.lastname: Jimenez-Velazquez
authors.forename: Yaakov
authors.initials: Y
authors.lastname: Stern
authors.forename: Benjamin
authors.initials: B
authors.lastname: Tycko
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Rogaeva
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Wakutani
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Kawarai
authors.forename: Peter
authors.initials: P
authors.lastname: St George-Hyslop
authors.forename: Richard
authors.initials: R
authors.lastname: Mayeux
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D053327:Apolipoprotein E4 / Q000235:genetics; D017691:Caribbean Region; D005260:Female; D008040:Genetic Linkage; D006630:Hispanic or Latino / Q000235:genetics*; D006801:Humans; D008126:Lod Score; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D053764:Presenilin-1 / Q000235:genetics
chemical_list: D053327:Apolipoprotein E4; C508853:PSEN1 protein, human; D053764:Presenilin-1