Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy

Department of Neurology, Philipps-Universität, Marburg, Germany.
Nature Genetics (Impact Factor: 29.65). 07/2011; 43(7):699-705. DOI: 10.1038/ng.859
Source: PubMed

ABSTRACT Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common of which is Alzheimer's disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 individuals with PSP (cases) and 3,247 controls (stage 1) followed by a second stage in which we genotyped 1,051 cases and 3,560 controls for the stage 1 SNPs that yielded P ≤ 10(-3). We found significant previously unidentified signals (P < 5 × 10(-8)) associated with PSP risk at STX6, EIF2AK3 and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response and for a myelin structural component.

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Available from: Irene Litvan, Jul 30, 2015
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    • "Additional support for a role for vesicular sorting and trafficking of membrane-associated proteins in PD biology has been provided by pathogenic mutations in LRRK2 [9], VPS35 resulting in autosomal dominant PD [10], and DNAJC6 mutations causing juvenile recessive PD [11]. Hoglinger et al., 2011 found three single nucleotide polymorphisms (SNPs) that were significantly associated with PSP risk at STX6, EIF2AK3 and MOBP. STX6 rs1411478 has an odds ratio of 0.73 (range from 0.65 to 0.81) and a p-value of 1.8 Â 10 À9 . "
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    ABSTRACT: A variant in Syntaxin 6 (a soluble N-ethylmaleimide-sensitive factor attachment protein receptor STX6) (rs1411478) has been shown to be associated with progressive supranuclear palsy (PSP). Although Parkinson's disease (PD) and PSP are distinct neurodegenerative diseases, they share some clinical and genetic features. In this study, we evaluated STX6 genetic variability in PD susceptibility in ethnically matched case-control series from Canada, Norway, Taiwan and Tunisia and we evaluated the presence of pathogenic mutations within families. No pathogenic mutations were found in STX6. Similarly, statistical analysis of rs1411478 failed to identify differences in genotype or allelic frequencies between cases and controls. Our results do not support a role for STX6 in PD.
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    • "Although linkage analysis along with candidate gene screening was traditionally the preferred method for gene discovery in inherited MDs (Paisan-Ruiz et al., 2004, 2005), these are not appropriate for families with largely reduced penetrance or reduced number of affected individuals. And even though there has been considerable success in identifying genetic risk factors for PD and PSP through the application of genome-wide association studies (GWAS; Simon-Sanchez et al., 2009; Hamza et al., 2010; Hoglinger et al., 2011), a detailed mapping through targeted resequencing (TR) is still required to further identify both high-risk alleles and haplotypes (Tucci et al., 2010; Freedman et al., 2011). By contrast, next-generation sequencing (NGS) technologies, such as exome sequencing (ES) and whole-genome sequencing (WGS), enable "
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    Frontiers in Genetics 05/2012; 3:75. DOI:10.3389/fgene.2012.00075
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    • "Additional associations included a series of SNPs on chromosome 17. Previous studies have noted an effect of chromo- some17 SNPs on expression of the MAPT gene that is associated with risk of PD and PSP (2011; Hoglinger et al., 2011 "
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