Human Molecular Genetics Advance Access published online on December 21, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl463
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Published by Oxford University Press 2006
Two sites in the MAPT region confer genetic risk for Guam ALS/PDC and dementia
1 Department of Medicine, Division of Gerontology & Geriatric Medicine 2 Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle Division, Seattle, WA 98108. 3 Department of Medicine, Division of Medical Genetics 4 Department of Anthropology, Laboratory of Biomedical Anthropology and Neurosciences, Binghamton University, SUNY, Binghamton, New York, 13902-6000 5 Department of Neuropathology, Tokyo Metropolitan Institute for Neuroscience, Tokyo, Japan 6 University of Guam, Mangilao, Guam, 96923 7 Department of Biostatistics 8 Department of Neurosciences, University of California, San Diego, La Jolla CA 92093-0662, USA 9 Department of Neurology and Pharmacology, University of Washington, Seattle, WA 98195.
* To whom correspondence should be addressed at: GRECC S-182B, Veterans Affairs Puget Sound Health Care System, 1660 S. Columbian Way, Seattle, WA 98108, USA. Tel: (206) 764-2701; Fax: (206) 764-2569; Email: zachdad{at}u.washington.edu
Received October 7, 2006; Revised December 6, 2006; Accepted December 6, 2006
Unusual forms of amyotrophic lateral sclerosis (ALS-G), Parkinsonism dementia complex (PDC-G), and dementia (GD), are found in Chamorros, the indigenous people of Guam. Neurofibrillary tangles composed of hyperphosphorylated tau are a neuopathologic feature of these closely related disorders. To determine if variation in the gene that encodes tau (MAPT), contributes to risk for these disorders, we genotyped 9 single nucleotide polymorphism (SNP) sites and one insertion/deletion in or 5' to MAPT in 54 ALS-G, 135 PDC-G, 153 GD, and 258 control subjects, all of whom are Chamorros. Variation at three SNPs (sites 2, 6, and 9) influenced risk for ALS-G, PDC-G and GD. SNP 2 acts through a dominant mechanism and is independent of risk conferred by SNPs 6 and 9, the latter two acting by a recessive mechanism. Persons with the high-risk SNP 6 and SNP 9 AC/AC diplotype had an increase in risk of 3-fold (95% CI = 1.10-8.25) for GD, 4-fold (95% CI = 1.40-11.64) for PDC-G, and 6-fold (95% CI = 1.44-32.14) for ALS-G, compared to persons with other diplotypes after adjusting for SNP 2. Carriers of the SNP 2 G allele had an increased risk of 1.6-fold (95% CI = 1.00-2.62) for GD, 2-fold (95% CI = 1.28-3.66) for PDC-G, and 1.5-fold (95% CI = 0.74-3.00) for ALS-G compared to non-carriers after adjusting for SNPs 6 and 9. Others have shown that SNP 6 is also associated with risk for progressive supranuclear palsy. These two independent cis-acting sites presumably influence risk by regulating MAPT expression.
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