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P3–163: Identification of a novel risk gene for progressive supranuclear palsy by a genome–wide scan of 500,288 SNPs
Author(s) -
Melquist Stacey,
Huentelman Matthew J.,
Craig David W.,
Baker Matt,
Crook Richard,
Pearson John V.,
Zisman Victoria L.,
Gass Jennifer,
Adamson Jennifer,
Szelinger Szabolcs,
Cournevaux Jason J.,
Can Ashley,
Coon Keith D.,
Dickson Dennis W.,
Stephan Dietrich,
Hutton Michael
Publication year - 2006
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2006.05.1431
Subject(s) - progressive supranuclear palsy , haplotype , genetics , biology , single nucleotide polymorphism , parkinsonism , tau protein , genotyping , gene , pathology , medicine , allele , genotype , alzheimer's disease , atrophy , disease
instable region. Twenty-eight SNPs were located in highly conserved regions distributed across the gene. Four conserved SNPs were located in the MAPT promoter and might affect expression, while one conserved SNP was located in intron 10 possibly affecting exon 10 splicing. Analysis of the haplotypic organization of the variants demonstrated little linkage disequilibrium across the complete gene and a recombination hotspot about 20 kb upstream of exon 1. We observed three common haplotypes, one of which represented the inverted haplotype H2A showing 424 sequence differences with the H1 haplotypes. The H1 haplotypes were defined by 152 sequence variants organized in two common haplotypes H1A and H1B and a large number of rare haplotypes. Conclusions: We identified many variants in the MAPT gene that, alone or in concert with each other, might result in haplotypedependent expression, splicing and stability of MAPT. This variability might contribute to the susceptibility of MAPT in many neurodegenerative brain diseases. However, the location of MAPT in a genomically instable region has resulted in a complex haplotypic organization, complicating genetic association studies.