Neurogenetics

, 9:51

Age-at-onset linkage analysis in Caribbean Hispanics with familial late-onset Alzheimer’s disease

  • Joseph H. Lee
  • Sandra Barral
  • Rong Cheng
  • Inara Chacon
  • Vincent Santana
  • Jennifer Williamson
  • Rafael Lantigua
  • Martin Medrano
  • Ivonne Z. Jimenez-Velazquez
  • Yaakov Stern
  • Benjamin Tycko
  • Ekaterina Rogaeva
  • Yosuke Wakutani
  • Toshitaka Kawarai
  • Peter St George-Hyslop
  • Richard Mayeux
Original Article

DOI: 10.1007/s10048-007-0103-3

Cite this article as:
Lee, J.H., Barral, S., Cheng, R. et al. Neurogenetics (2008) 9: 51. doi:10.1007/s10048-007-0103-3

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-ɛ4 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-ɛ4 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.

Keywords

Alzheimer’s disease Age at onset Linkage analysis Family-based association analysis APOE 

Supplementary material

10048_2007_103_Fig1_ESM.gif (62 kb)
Fig. S1a

Probable&PossibleAD. C1-C10 (GIF 63 KB)

10048_2007_103_Fig2_ESM.gif (61 kb)
Fig. S1b

Probable&Possible. C11-C22 (GIF 62 KB)

10048_2007_103_Fig3_ESM.gif (65 kb)
Fig. S2a

Probable. C1-C10 (GIF 66 KB)

10048_2007_103_Fig4_ESM.gif (60 kb)
Fig. S2b

Probable. C11-C22 (GIF 61 KB)

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Joseph H. Lee
    • 1
    • 2
    • 7
  • Sandra Barral
    • 1
  • Rong Cheng
    • 1
    • 2
  • Inara Chacon
    • 2
  • Vincent Santana
    • 1
    • 2
  • Jennifer Williamson
    • 1
    • 2
  • Rafael Lantigua
    • 1
    • 5
  • Martin Medrano
    • 8
  • Ivonne Z. Jimenez-Velazquez
    • 9
  • Yaakov Stern
    • 1
    • 2
    • 3
    • 4
  • Benjamin Tycko
    • 1
    • 6
  • Ekaterina Rogaeva
    • 10
  • Yosuke Wakutani
    • 10
  • Toshitaka Kawarai
    • 10
  • Peter St George-Hyslop
    • 10
  • Richard Mayeux
    • 1
    • 2
    • 3
    • 4
    • 7
  1. 1.The Taub Institute on Alzheimer’s Disease and the Aging BrainColumbia UniversityNew YorkUSA
  2. 2.Gertrude H. Sergievsky CenterColumbia UniversityNew YorkUSA
  3. 3.The Department of Neurology, College of Physicians and SurgeonsColumbia UniversityNew YorkUSA
  4. 4.The Department of Psychiatry, College of Physicians and SurgeonsColumbia UniversityNew YorkUSA
  5. 5.The Department of Medicine, College of Physicians and SurgeonsColumbia UniversityNew YorkUSA
  6. 6.The Department of Pathology, College of Physicians and SurgeonsColumbia UniversityNew YorkUSA
  7. 7.The Department of Epidemiology, School of Public HealthColumbia UniversityNew YorkUSA
  8. 8.The Universidad Tecnologica de SantiagoSantiago de los CaballerosDominican Republic
  9. 9.The Department of Internal MedicineUniversity of Puerto Rico School of MedicineSan JuanPuerto Rico
  10. 10.Centre for Research in Neurodegenerative Diseases, Department of MedicineUniversity of Toronto, and Toronto Western Hospital Research InstituteTorontoCanada

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