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

Abstract

Objective-An inversion polymorphism of approximately 900kb 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.Methods-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.Results-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 × 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 NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript difference between cases and control subjects in the overall frequency distribution of H1 subhaplotypes.Interpretation-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.The microtubule-associated protein tau, encoded by the MAPT gene, is primarily expressed in neurons and plays a key role in the organization and integrity of the cytoskeleton.1 ,2 Filamentous neuronal tau inclusions define a set of neurodegenerative diseases collectively known as the tauopathies, which include Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal dementia with parkinsonism linked to chromosome 17. 1, 2 MAPT sequence variation was first linked to the etiopathogenesis of tauopathies by the discovery of mutations resulting in frontotemporal dementia with parkinsonism linked to chromosome 17, and subsequently an extended common haplotype (H1) across the gene was shown to associate with disease risk in PSP and CBD. 3-7Though Parkinson's disease (PD) shares some clinical features with the tauopathies, it has been assigned to a distinct subset of neurodegenerative diseases (the α-synucleinopathies) by histopathology because it is characterized by intraneuronal accumulation of α-synuclein, rather than tau. 8 Thus, initial reports that the MAPT H1 haplotype was also associated with PD were intriguing but met with some skepticism. Since then the association between MAPT variants and PD has remained tenuous with a number of small case-control studies report...

Genome-wide association study confirms extant PD risk loci among the Dutch

“…This is probably because of the relatively small size of the sample used for these experiments, as this locus is a well-known PD risk locus among Europeans. 5,7,9,23,65,66 If the same hypothesis as that presented for GAK/DGKQ is applied, five out of the nine tested SNPs would be borderline significant (in the range of 10 À3 ) supporting a role of this locus in the development of PD among the Dutch.…”

“…9,18 To determine which of the associated alleles in the MAPT locus were present in H1 (previously associated with PD [19][20][21][22][23][24] ) a two-locus haplotype association analysis of rs1981997 and SNPs in the MAPT region was carried out using PLINK. 15 Although we are aware that the sample size of this cohort has a limited power and a GWAS would probably fail to find any associated locus after correcting for 514 799 independent tests, we decided to carry out this analysis to look for specific PD risk loci in the Dutch population.…”

Genetics of Parkinson disease

“…209,210 This was recently confirmed by another large study of 1762 PD patients and 2010 control subjects and was found to be consistent across age, gender, and family history. 211 The deleterious haplotype (H1) and the protective haplotype (H2) actually represent groups of subhaplotypes that have formed independently; however, associations with any of these subhaplotypes have so far been inconsistent. 211 The single-nucleotide polymorphisms that define the parent haplotypes of H1 and H2 are in complete linkage disequilibrium with each other (r 2 ϭ 1), indicating that the functional variation could be anywhere within this large 900-kb region and not necessarily within any segment of MAPT.…”

“…211 The deleterious haplotype (H1) and the protective haplotype (H2) actually represent groups of subhaplotypes that have formed independently; however, associations with any of these subhaplotypes have so far been inconsistent. 211 The single-nucleotide polymorphisms that define the parent haplotypes of H1 and H2 are in complete linkage disequilibrium with each other (r 2 ϭ 1), indicating that the functional variation could be anywhere within this large 900-kb region and not necessarily within any segment of MAPT. Complex permutations of alternative splicing lead to many different isoforms of tau; so if the association with H1 is due to variation that were to upset this delicate balance of isoforms, it may help to explain the variety of different neurodegenerative phenotypes that exhibit tau pathology.…”

Population genetic and Alzheimer’s disease related gene-interaction studies on 17q21.31 genomic inversion

“…clade is involved in pathophysiologic processes probably as a consequence of more various alternative splicing and expression with clear genetic association to Parkinson's disease (Zabetian et al, 2007), progressive supranuclear palsy , argyrophilic grain disease (Fujino et al, 2005), corticobasal degeneration , frontotemporal dementia (Verpillat et al, 2002) and lower regional cerebral gray matter volume in healthy individuals (Canu et al, 2009). Its association to Alzheimer's disease is also supported by many findings (Myers et al, 2007) but there are controversial results too (Caffrey and Wade-Martins, 2012).…”