TAU as a susceptibility gene for amyotropic lateral sclerosis-parkinsonismdementia complex of Guam

Background: A Guam variant of amyotrophic lateral sclerosis (ALS-G) and par kinsonism. dementia complex (PDC-G) are found in the Chamorro people of Gua m. Both disorders have overlapping neuropathologic findings, with neurofibr illary tangles in spinal cord and brain. The cause of ALS-G-PDC-G is unknow n, although inheritance and environment appear important. Because neurofibr illary tangles containing tau protein are present in ALS-G-PDC-G, and becau se mutations in the tau gene (TAU) cause autosomal dominant frontotemporal dementia, TAU was examined as a candidate gene for ALS-G-PDC-G. Methods: TAU was evaluated by DNA sequence analysis in subjects with ALS-G- PDC-G, by linkage analysis of TAU polymorphisms in an extended pedigree fro m the village of Umatac, and by evaluation of linkage disequilibrium with p olymorphic markers flanking and within TAU. Results: Linkage disequilibrium between ALS-G-PDC-G and the TAU polymorphis m CA3662 was observed. For this 2-allele system, PDC and ALS cases were sig nificantly less likely than Guamanian controls to have the 1 allele (4.9% a nd 2% vs 11.5%, respectively; Fisher exact P=.007). DNA sequence analysis o f TAU coding regions did not demonstrate a mutation responsible for ALS-C-P DC-G. Analysis of TAU genotypes in an extended pedigree of subjects from Um atac showed obligate recombinants between TAU and ALS-G-PDC-G. Linkage anal ysis of the Umatac pedigree indicates that TAU is not the major gene for AL S-G-PDC-G. Conclusions: The genetic association between ALS-GPDC-G implicates TAU in t he genetic susceptibility to ALS-G-PDC-G. TAU may be a modifying gene incre asing risk for ALS-G-PDC-G in the presence of another, as yet, unidentified gene.