Neuroscience 2005 Abstract
| Presentation Number: | 1005.7 |
|---|---|
| Abstract Title: | Dissection of the tau gene haplotype association with PSP, CBD, and AD. |
| Authors: |
de Silva, R.*1,3
; Pittman, A. M.1
; Myers, A. J.2
; Williams, D. R.1
; Fung, H. C.1
; Kaleem, M.2
; Marlowe, L.2
; Duckworth, J.2
; Leung, D.2
; Wood, N. W.3
; Hardy, J.1,2
; Lees, A. J.1
1Reta Lila Weston Inst. of Neurological Studies/UCL, London, United Kingdom 2MD, Windeyer Building 6 Cleveland Street, W1T 4JF, 3USA, Windeyer Building 6 Cleveland Street, W1T 4JF, |
| Primary Theme and Topics |
Disorders of the Nervous System - Neurodegenerative and Movement Disorders -- Parkinson's disease: Other |
| Session: |
1005. Parkinson's Disease: Other Clinical Poster |
| Presentation Time: | Wednesday, November 16, 2005 3:00 PM-4:00 PM |
| Location: | Washington Convention Center - Hall A-C, Board # PP9 |
| Keywords: | parkinsonism, alzheimer, neurodegeneration, genetics |
We aimed to establish the pathogenic basis of the association of the tau gene, MAPT, H1 haplotype with progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). EM analysis of HapMap SNP data for MAPT, showed considerable diversity of the H1 clade with 21 rare (<5%) and 3 common (>10%) haplotypes. Only one of the latter represents H2. We then typed a set of 6 haplotype-tagging SNPs (htSNPs) capturing most of this diversity, in large PSP and CBD case-control cohorts of UK and US origin. We confirmed the strong association with PSP of the H1 haplotype (UK PSP: p=1.14x10-5; US PSP: p=4.02x10-8). In PSP we identified differences in association of the H1H1 genotype between Richardson’s syndrome, RS (OR 13.2; 95%CI 3.0-57.2; p<0.001) and PSP-parkinsonism, PSP-P (OR 4.5; 95%CI 1.3-16.0; p=0.018)1.
The H2 haplotype is negatively associated, ie is protective (UK PSP: p=1.1x10-5; US PSP: p=4.02x10-8). The H1-specific htSNPs, rs242557 and rs2471738, are highly associated with PSP and CBD (UK PSP: p=0.012 & 0.001; US PSP: p=2.91x10-9 & 1.87x10-5; US CBD: p=0.002 & 0.005, respectively). Interestingly, the same htSNPs are associated with an US series of late-onset Alzheimer’s disease (AD) (p=0.038 & p=0.024), although del-In9 (H1) is not.
Two common haplotypes, A and C, formed with the htSNPs, are strongly associated with PSP. Haplotype A, representing H2, is negatively associated (UK PSP: p=1.46x10-5; US PSP: 9.5x10-9) but not AD. Haplotype C is positively associated with UK PSP (p=0.001), US PSP (p=9.5x10-9) and AD (p=0.018). This association implicates a region of ~56kb of MAPT from upstream of exon 1 to exon 9. We are currently carrying out analyses in the RS and PSP-P sub-groups and directly sequencing the candidate region in haplotype A and C homozygotes in PSP and AD.
1. Williams, DR, et al. Brain. 2005 (Adv. ePub).
The H2 haplotype is negatively associated, ie is protective (UK PSP: p=1.1x10-5; US PSP: p=4.02x10-8). The H1-specific htSNPs, rs242557 and rs2471738, are highly associated with PSP and CBD (UK PSP: p=0.012 & 0.001; US PSP: p=2.91x10-9 & 1.87x10-5; US CBD: p=0.002 & 0.005, respectively). Interestingly, the same htSNPs are associated with an US series of late-onset Alzheimer’s disease (AD) (p=0.038 & p=0.024), although del-In9 (H1) is not.
Two common haplotypes, A and C, formed with the htSNPs, are strongly associated with PSP. Haplotype A, representing H2, is negatively associated (UK PSP: p=1.46x10-5; US PSP: 9.5x10-9) but not AD. Haplotype C is positively associated with UK PSP (p=0.001), US PSP (p=9.5x10-9) and AD (p=0.018). This association implicates a region of ~56kb of MAPT from upstream of exon 1 to exon 9. We are currently carrying out analyses in the RS and PSP-P sub-groups and directly sequencing the candidate region in haplotype A and C homozygotes in PSP and AD.
1. Williams, DR, et al. Brain. 2005 (Adv. ePub).
Supported by Reta Lila Weston Trust
Sample Citation:
[Authors]. [Abstract Title]. Program No. XXX.XX. 2005 Neuroscience Meeting Planner. Washington, DC: Society for Neuroscience, 2005. Online.
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