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P3–161: Increased MAPT expression is associated with progressive supranuclear palsy
Author(s) -
Pittman Alan,
Myers Amanda J.,
Hardy John,
Wood Nicholas W.,
Lees Andrew,
Silva Rohan
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.2006.05.1429
Subject(s) - progressive supranuclear palsy , haplotype , biology , genetics , single nucleotide polymorphism , promoter , linkage disequilibrium , exon , intron , gene , alternative splicing , rna splicing , allele , gene expression , genotype , rna , atrophy
MAPT genomically to identify the LD structure underlying MAPT H1 and to generate a high-density SNP map for association studies. This provided us with 153 H1 SNPs and a panel of 15 haplotype tagging SNPs capturing 95% of the haplotype diversity in MAPT. Results: We did not identify association of the extended MAPT haplotypes in Belgian and French PD patient-control populations. However, in the Belgian population we identified significant association for earlyand late-onset PD (cut-off age 55 years) with H1 specific subhaplotypes and we replicated this finding in a French early-onset PD sample. In both populations, high-density SNP finemapping localized the early-onset PD-risk to an overlapping 3.5 kb region surrounding the alternatively spliced exon 10 (PBelgian 0.006; PFrench 0.0002). Also, in the Belgian late-onset PD sample significant association was detected with a 1 kb region in the intron 0 regulatory region of MAPT upstream of exon 1 (PBelgian 0.002). Currently, these significant findings are followed up by association analyses in earlyand late-onset European PD populations from Ireland and Norway. Conclusions: Our findings reveal an important role for genetic variants in MAPT in pathogenesis of PD. The selective finemapping of the MAPT H1 associated risk to MAPT intron 0 and the alternatively spliced exon 10 further suggests that MAPT variants contribute to PD-risk by affecting alternative MAPT splicing or by altering regulation of MAPT expression.