Human Molecular Genetics Advance Access originally published online on December 21, 2006
Human Molecular Genetics 2007 16(3):295-306; 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 and Geriatric Medicine, 2 Department of Medicine, Division of Medical Genetics, 3 Department of Biostatistics, 4 Department of Neurology and Pharmacology, University of Washington, Seattle, WA 98195, USA, 5 Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle Division, Seattle, WA 98108, USA, 6 Department of Anthropology, Laboratory of Biomedical Anthropology and Neurosciences, Binghamton University, SUNY-Binghamton, NY 13902-6000, USA, 7 Department of Neuropathology, Tokyo Metropolitan Institute for Neuroscience, Tokyo, Japan, 8 University of Guam, Mangilao, Guam 96923, USA and 9 Department of Neurosciences, University of California, San Diego, La Jolla CA 92093-0662, USA
* 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: +1 2067642701; Fax: +1 2067642569; Email: zachdad{at}u.washington.edu
Received October 7, 2006; Accepted December 6, 2006
Unusual forms of amyotrophic lateral sclerosis (ALS-G), Parkinsonism dementia complex (PDC-G) and Guam dementia (GD) are found in Chamorros, the indigenous people of Guam. Neurofibrillary tangles composed of hyperphosphorylated tau are a neuropathologic feature of these closely related disorders. To determine if variation in the gene that encodes microtubule-associated protein tau gene (MAPT) contributes to risk for these disorders, we genotyped nine single nucleotide polymorphism (SNP) sites and one insertion/deletion in the 5' end of 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. SNP2 acts through a dominant mechanism and is independent of the risk conferred by SNPs 6 and 9, the latter two acting by a recessive mechanism. Persons with the high-risk SNP6 and SNP9 AC/AC diplotype had an increased risk of 3-fold [95% confidence interval (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 SNP2. Carriers of the SNP2 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 SNP6 is also associated with risk for progressive supranuclear palsy. These two independent cis-acting sites presumably influence risk for Guam neuro-degenerative disorders by regulating MAPT expression.
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