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Two sites in the MAPT region confer genetic risk for Guam ALS/PDC and dementia.

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.