Association analysis of MAPT H1 haplotype and subhaplotypes in Parkinson's disease

Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA.
Annals of Neurology (Impact Factor: 9.98). 08/2007; 62(2):137-44. DOI: 10.1002/ana.21157
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An inversion polymorphism of approximately 900 kb on chromosome 17q21, which includes the microtubule-associated protein tau (MAPT) gene defines two haplotype clades, H1 and H2. Several small case-control studies have observed a marginally significant excess of the H1/H1 diplotype among patients with Parkinson's disease (PD), and one reported refining the association to a region spanning exons 1 to 4 of MAPT. We sought to replicate these findings.
We genotyped 1,762 PD patients and 2,010 control subjects for a single nucleotide polymorphism (SNP) that differentiates the H1 and H2 clades. We also analyzed four SNPs that define subhaplotypes within H1 previously reported to associate with PD or other neurodegenerative disorders.
After adjusting for age, sex, and site, we observed a robust association between the H1/H1 diplotype and PD risk (odds ratio for H1/H1 vs H1/H2 and H2/H2, 1.46; 95% confidence interval, 1.25-1.69; p = 8 x 10(-7)). The effect was evident in both familial and sporadic subgroups, men and women, and early- and late-onset disease. Within H1/H1 individuals, there was no significant difference between cases and control subjects in the overall frequency distribution of H1 subhaplotypes.
Our data provide strong evidence that the H1 clade, which contains MAPT and several other genes, is a risk factor for PD. However, attributing this finding to variants within a specific region of MAPT is premature. Thorough fine-mapping of the H1 clade in large numbers of individuals is now needed to identify the underlying functional variant(s) that alter susceptibility for PD.

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Available from: John Nutt, Apr 11, 2015
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    • "Our data suggest that saitohin rs62063857 polymorphism is robustly associated with Parkinson's disease in overall Parkinson's disease patients as well as male and female Parkinson's patients. Some previous studies were highly correlated with our study and gave a robust association with Parkinson's disease (Skipper et al. 2004; Zabetian et al. 2007, Wider et al. 2010 "
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    ABSTRACT: Saitohin gene found within the tau gene is thought to play a role in the pathogenesis of neurodegenerative diseases. The rs62063857 polymorphism originally found in the saitohin gene seems to be the responsible SNP in this event. This polymorphism is studied mostly in patients with Alzheimer's disease. Data on Parkinson's disease are scarce. Therefore, we examined the rs62063857 polymorphism in 583 Parkinson's disease patients (347 male and 236 female) and 396 healthy controls (238 male and 158 female) by a polymerase chain reaction and restriction fragment length polymorphism method to see whether it was associated with Parkinson's disease from the City of Istanbul, Turkey. The G allele frequency was 22 % in overall controls and 16 % in Parkinson's disease patients. In this study, the saitohin rs62063857 polymorphism was associated with Parkinson's disease (χ2 = 16.765; P = 0.000). Individuals with the AA genotype showed 1.7-fold increased risk for Parkinson's disease (χ2 = 16.680; P = 0.000), whereas individuals with the AG genotype revealed protection against Parkinson's disease (χ2 = 14.554; P = 0.000). After the stratification analysis according to gender, both male and female PD patients showed association with the alleles and genotypes of the rs62063857 polymorphism of the saitohin gene (χ2 = 9.476, P = 0.009; χ2 = 7.593, P = 0.022, respectively). When the Parkinson's patients were divided into two groups with regard to onset of the disease, both groups showed association with the disease. The Parkinson's patients with disease onset below 65 years of age showed 1.8-fold increased risk for the disease. The Parkinson's patients with disease onset over 65 showed more robust association with a 2.051-fold increased risk for the disease. Consequently, the rs62063857 polymorphism of the saitohin gene is a genetic risk factor for Parkinson's disease. Hence, this polymorphism may play a role in the etiology of Parkinson's disease.
    Cellular and Molecular Neurobiology 08/2014; 35(1). DOI:10.1007/s10571-014-0102-5 · 2.51 Impact Factor
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    • "The MAPT H1 haplotype is associated with an increased risk of PD [17]. In addition, individuals homozygous for MAPT H1/H1 have an increased susceptibility to develop PD compared to those bearing the heterozygous H1/H2 genotype [59]. Furthermore, some of the MAPT variants appear to increase overall Tau expression [25]. "
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    ABSTRACT: While a number of genome-wide association studies have identified microtubule-associated protein tau as a strong risk factor for Parkinson’s disease (PD), little is known about the mechanism through which human tau can predispose an individual to this disease. Here, we demonstrate that expression of human wild-type tau is sufficient to disrupt the survival of dopaminergic neurons in a Drosophila model. Tau triggers a synaptic pathology visualized by vesicular monoamine transporter-pHGFP that precedes both the age-dependent formation of tau-containing neurofibrillary tangle-like pathology and the progressive loss of DA neurons, thereby recapitulating the pathological hallmarks of PD. Flies overexpressing tau also exhibit progressive impairments of both motor and learning behaviors. Surprisingly, contrary to common belief that hyperphosphorylated tau could aggravate toxicity, DA neuron degeneration is alleviated by expressing the modified, hyperphosphorylated tauE14. Together, these results show that impairment of VMAT-containing synaptic vesicle, released to synapses before overt tauopathy may be the underlying mechanism of tau-associated PD and suggest that correction or prevention of this deficit may be appropriate targets for early therapeutic intervention. Electronic supplementary material The online version of this article (doi:10.1007/s00401-013-1105-x) contains supplementary material, which is available to authorized users.
    Acta Neuropathologica 03/2013; 125(5). DOI:10.1007/s00401-013-1105-x · 10.76 Impact Factor
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    • "Listed in Figure 2 are the most significant SNPs within a 2.5 Mb chromosomal region surrounding each of the 25 PD candidate genes and estimate of the number of false discoveries evaluated at the probability at which the SNP was claimed significant [21]. It can be seen that all the three methods detected the SNP, rs2736990, within the PD candidate gene SNCA[22] on human chromosome 4q21 as well as the SNP rs199533, just 0.72 Mb distant from the PD candidate gene MAPT[23] on chromosome 17q21 with negligible risk of being false positives. In addition to these, Method 1 discovered two additional SNPs located 1.18 Mb and 0.18 Mb from the PD candidates, FGF20[18] and PARK8[19] respectively without invoking the risk of false positive. "
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    ABSTRACT: Background The theoretical basis of genome-wide association studies (GWAS) is statistical inference of linkage disequilibrium (LD) between any polymorphic marker and a putative disease locus. Most methods widely implemented for such analyses are vulnerable to several key demographic factors and deliver a poor statistical power for detecting genuine associations and also a high false positive rate. Here, we present a likelihood-based statistical approach that accounts properly for non-random nature of case–control samples in regard of genotypic distribution at the loci in populations under study and confers flexibility to test for genetic association in presence of different confounding factors such as population structure, non-randomness of samples etc. Results We implemented this novel method together with several popular methods in the literature of GWAS, to re-analyze recently published Parkinson’s disease (PD) case–control samples. The real data analysis and computer simulation show that the new method confers not only significantly improved statistical power for detecting the associations but also robustness to the difficulties stemmed from non-randomly sampling and genetic structures when compared to its rivals. In particular, the new method detected 44 significant SNPs within 25 chromosomal regions of size < 1 Mb but only 6 SNPs in two of these regions were previously detected by the trend test based methods. It discovered two SNPs located 1.18 Mb and 0.18 Mb from the PD candidates, FGF20 and PARK8, without invoking false positive risk. Conclusions We developed a novel likelihood-based method which provides adequate estimation of LD and other population model parameters by using case and control samples, the ease in integration of these samples from multiple genetically divergent populations and thus confers statistically robust and powerful analyses of GWAS. On basis of simulation studies and analysis of real datasets, we demonstrated significant improvement of the new method over the non-parametric trend test, which is the most popularly implemented in the literature of GWAS.
    BMC Genomics 02/2013; 14(1):88. DOI:10.1186/1471-2164-14-88 · 3.99 Impact Factor
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