Association analysis of MAPT H1 haplotype and subhaplotypes in Parkinson's disease
Corresponding Author
Cyrus P. Zabetian MD, MS
Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA
Department of Neurology, University of Washington School of Medicine, Seattle, WA
Geriatric Research Education and Clinical Center S-182, VA Puget Sound Health Care System, 1660 South Columbian Way, Seattle, WA 98108Search for more papers by this authorCarolyn M. Hutter MS
Department of Epidemiology, University of Washington School of Public Health and Community Medicine, Seattle, WA
Search for more papers by this authorStewart A. Factor DO
Department of Neurology, Emory University School of Medicine, Atlanta, GA
Search for more papers by this authorJohn G. Nutt MD
Department of Neurology, Oregon Health and Science University, Portland, OR
Search for more papers by this authorDonald S. Higgins MD
Parkinson's Disease and Movement Disorder Clinic, Albany Medical Center, Albany, NY
Search for more papers by this authorAlida Griffith MD
Booth Gardner Parkinson's Care Center, Evergreen Hospital Medical Center, Kirkland, WA
Search for more papers by this authorBerta C. Leis RN, PhD
Booth Gardner Parkinson's Care Center, Evergreen Hospital Medical Center, Kirkland, WA
Search for more papers by this authorDenise M. Kay PhD
Genomics Institute, Wadsworth Center, New York State Department of Health, Albany, NY
Search for more papers by this authorDora Yearout BS
Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA
Department of Neurology, University of Washington School of Medicine, Seattle, WA
Search for more papers by this authorJennifer S. Montimurro BS
Genomics Institute, Wadsworth Center, New York State Department of Health, Albany, NY
Search for more papers by this authorKaren L. Edwards PhD
Department of Epidemiology, University of Washington School of Public Health and Community Medicine, Seattle, WA
Search for more papers by this authorAli Samii MD
Department of Neurology, University of Washington School of Medicine, Seattle, WA
Parkinson's Disease Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA
Search for more papers by this authorHaydeh Payami PhD
Genomics Institute, Wadsworth Center, New York State Department of Health, Albany, NY
Search for more papers by this authorCorresponding Author
Cyrus P. Zabetian MD, MS
Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA
Department of Neurology, University of Washington School of Medicine, Seattle, WA
Geriatric Research Education and Clinical Center S-182, VA Puget Sound Health Care System, 1660 South Columbian Way, Seattle, WA 98108Search for more papers by this authorCarolyn M. Hutter MS
Department of Epidemiology, University of Washington School of Public Health and Community Medicine, Seattle, WA
Search for more papers by this authorStewart A. Factor DO
Department of Neurology, Emory University School of Medicine, Atlanta, GA
Search for more papers by this authorJohn G. Nutt MD
Department of Neurology, Oregon Health and Science University, Portland, OR
Search for more papers by this authorDonald S. Higgins MD
Parkinson's Disease and Movement Disorder Clinic, Albany Medical Center, Albany, NY
Search for more papers by this authorAlida Griffith MD
Booth Gardner Parkinson's Care Center, Evergreen Hospital Medical Center, Kirkland, WA
Search for more papers by this authorBerta C. Leis RN, PhD
Booth Gardner Parkinson's Care Center, Evergreen Hospital Medical Center, Kirkland, WA
Search for more papers by this authorDenise M. Kay PhD
Genomics Institute, Wadsworth Center, New York State Department of Health, Albany, NY
Search for more papers by this authorDora Yearout BS
Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA
Department of Neurology, University of Washington School of Medicine, Seattle, WA
Search for more papers by this authorJennifer S. Montimurro BS
Genomics Institute, Wadsworth Center, New York State Department of Health, Albany, NY
Search for more papers by this authorKaren L. Edwards PhD
Department of Epidemiology, University of Washington School of Public Health and Community Medicine, Seattle, WA
Search for more papers by this authorAli Samii MD
Department of Neurology, University of Washington School of Medicine, Seattle, WA
Parkinson's Disease Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA
Search for more papers by this authorHaydeh Payami PhD
Genomics Institute, Wadsworth Center, New York State Department of Health, Albany, NY
Search for more papers by this authorAbstract
Objective
An inversion polymorphism of approximately 900kb on chromosome 17q21, which includes the microtubule-associated protein tau (MAPT) gene defines two haplotype clades, H1 and H2. Several small case–control studies have observed a marginally significant excess of the H1/H1 diplotype among patients with Parkinson's disease (PD), and one reported refining the association to a region spanning exons 1 to 4 of MAPT. We sought to replicate these findings.
Methods
We genotyped 1,762 PD patients and 2,010 control subjects for a single nucleotide polymorphism (SNP) that differentiates the H1 and H2 clades. We also analyzed four SNPs that define subhaplotypes within H1 previously reported to associate with PD or other neurodegenerative disorders.
Results
After adjusting for age, sex, and site, we observed a robust association between the H1/H1 diplotype and PD risk (odds ratio for H1/H1 vs H1/H2 and H2/H2, 1.46; 95% confidence interval, 1.25–1.69; p = 8 × 10−7). The effect was evident in both familial and sporadic subgroups, men and women, and early- and late-onset disease. Within H1/H1 individuals, there was no significant difference between cases and control subjects in the overall frequency distribution of H1 subhaplotypes.
Interpretation
Our data provide strong evidence that the H1 clade, which contains MAPT and several other genes, is a risk factor for PD. However, attributing this finding to variants within a specific region of MAPT is premature. Thorough fine-mapping of the H1 clade in large numbers of individuals is now needed to identify the underlying functional variant(s) that alter susceptibility for PD. Ann Neurol 2007
Supporting Information
This article includes supplementary materials available via the Internet at http://www.interscience.wiley.com/jpages/0364-5134/suppmat
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| ANA21157_SuppTable1.doc41.5 KB | Supporting Information file ANA21157_SuppTable1.doc |
| ANA21157_SuppTable2.doc66 KB | Supporting Information file ANA21157_SuppTable2.doc |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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