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: 11.91). 08/2007; 62(2):137-44. DOI: 10.1002/ana.21157
Source: PubMed

ABSTRACT 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 · 2.20 Impact Factor
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    • "In this study, we included 22 well-characterized DLB cases. In agreement with previous studies in LB diseases (Compta et al., 2011; Elbaz et al., 2011; Setó-Salvia et al., 2011; Zabetian et al., 2007) we did not find any differences between MAPT haplotype groups in clinical data, APOE ␧4 genotype, or concomitant AD-related pathology. The finding of enhanced ␣-synuclein deposition in DLB is clinically relevant because the MAPT H1 haplotype has been associated with other synucleinopathies, such as PD and PDD (Hardy, 2010). "
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    ABSTRACT: The microtubule-associated protein tau (MAPT) H1 haplotype has been identified as a genetic risk factor for synucleinopathies. However, whether it modulates tau or α-synuclein pathology remains unknown. Our aim was to investigate the relationship between MAPT haplotypes and pathologic aggregates of tau and α-synuclein in pathologically confirmed cases of dementia with Lewy bodies (DLB). Twenty-two cases fulfilling clinical and neuropathological criteria for DLB were included. Clinical and neuropathological data were collected, and APOE and MAPT genotypes were determined. Tau and α-synuclein pathology was assessed semiquantitatively in 17 brain areas and total scores were calculated. DLB H1/H1 (n = 12) and H2 carriers (n = 10) did not differ in demographics, clinical variables, concomitant Alzheimer's pathology, or APOE genotype. Total α-synuclein scores were significantly increased in the H1/H1 group (p = 0.011), largely due to an increase in brainstem regions. This difference was driven by an increase in Lewy bodies and diffuse and punctuate cytoplasmatic α-synuclein aggregates (p = 0.007 and p = 0.025 respectively). These findings provide a mechanistic link for the genetic association between MAPT haplotypes and synucleinopathies.
    Neurobiology of aging 07/2012; 34(3). DOI:10.1016/j.neurobiolaging.2012.06.015 · 4.85 Impact Factor
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    • "The H1 and H2 structures represent different clades of haplotypes without any evidence of inter-recombination events, probably due to the inverted status of H2. The H1 configuration is associated with Alzhei mer's disease [Myers et al., 2005], progressive supranuclear palsy [Conrad et al., 1997], and Parkinson disease [Zabetian et al., 2007], while the H2 haplotype is linked to the recurrent deletion events associated with the 17q21.31 microdeletion syndrome. "
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    ABSTRACT: The chromosomal band 17q21.31, containing the microtubule-associated protein tau (MAPT) gene, is a hotspot for chromosomal rearrangements. It is known to contain a common inversion polymorphism of approximately 900 kb in populations with European ancestry. The inverted configuration is linked to a distinct MAPT haplotype, H2, which is relatively common in Europeans but nearly absent in Asian and African populations. Recent studies have demonstrated that the H2 haplotype is ancestral in hominoids, and under positive selection in Europeans. This haplotype is also linked to events leading to the 17q21.31 microdeletion syndrome, one of the most common causes of 'idiopathic' mental retardation in people of European descent. We performed direct analysis of the chromosome structure by fluorescence in situ hybridization and observed heterozygosity of the inversion status for the H2 chromosomes, but not for the H1 haplotype. Inversion heterozygosity was also observed in a mother homozygous for the H2 haplotype, who transmitted the chromosome with the deletion to a proband with 17q21.31 microdeletion syndrome. Our results highlight an allele-specific sensitivity to chromosome rearrangements and suggest that it is the heterozygosity of inversion status that predisposes to the 17q21.31 microdeletion syndrome.
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