Linkage disequilibrium fine mapping and haplotype association analysis of the tau gene in progressive supranuclear palsy and corticobasal degeneration

Abstract

Background: The haplotype H1 of the tau gene, MAPT, is highly associated with progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Objective: To investigate the pathogenic basis of this association. Methods: Detailed linkage disequilibrium and common haplotype structure of MAPT were examined in 27 CEPH trios using validated HapMap genotype data for 24 single nucleotide polymorphisms (SNPs) spanning MAPT. Results: Multiple variants of the H1 haplotype were resolved, reflecting a far greater diversity of MAPT than can be explained by the H1 and H2 clades alone. Based on this, six haplotype tagging SNPs (htSNPs) that capture 95% of the common haplotype diversity were used to genotype well characterised PSP and CBD case-control cohorts. In addition to strong association with PSP and CBD of individual SNPs, two common haplotypes derived from these htSNPs were identified that are highly associated with PSP: the sole H2 derived haplotype was underrepresented and one of the common H1 derived haplotypes was highly associated, with a similar trend observed in CBD. There were powerful and highly significant associations with PSP and CBD of haplotypes formed by three H1 specific SNPs. This made it possible to define a candidate region of at least ,56 kb, spanning sequences from upstream of MAPT exon 1 to intron 9. On the H1 haplotype background, these could harbour the pathogenic variants. Conclusions: The findings support the pathological evidence that underlying variations in MAPT could contribute to disease pathogenesis by subtle effects on gene expression and/or splicing. They also form the basis for the investigation of the possible genetic role of MAPT in Parkinson's disease and other tauopathies, including Alzheimer's disease.

Tau Isoform Composition Influences Rate and Extent of Filament Formation

“…In particular, the strong increase in aggregation propensity associated with the fourth microtubule binding repeat more than compensates for the depletion of 1N isoforms in AD (56). In contrast, haplotype H2, which is protective against PSP (7,8), supports increased inclusion of exon 3 as well as decreased inclusion of exon 10 relative to H1 (47,55). Moreover, levels of 2N forms of Tau are depressed in the Tau aggregates that accumulate in PSP (58 -60).…”

“…Despite this canonical expression pattern, the six central nervous system Tau isoforms vary in relative amounts depending on both cis and trans gene regulatory mechanisms. The MAPT haplotype, for example, influences levels of both exon 3 and exon 10 containing transcripts, with the H1 haplotypes that favor inclusion of exon 10 being associated with the corticobasal degeneration and PSP forms of FTLD (6 -8), and the H2 haplotype that favors exon 3 inclusion being protective against PSP (7,8). Exon 10 inclusion also is modulated by certain intronic point mutations, with those that increase exon 10 containing transcripts, causing familial forms of FTLD (9,10).…”

Fine mapping of the MAPT locus using quantitative trait analysis identifies possible causal variants in Alzheimer's disease

“…11 These two clades can be delineated via the a 238 bp insertion/deletion polymorphism within intron 9 (del-In9). 10,12,13 Association studies of H1 versus H2, in AD have to date produced largely negative findings. [13][14][15][16] Recent studies have reported that whereas the H2 haplotype is in fact a single nonrecombining haplotype, the more common H1 haplotype is more diverse, showing typical linkage disequilibrium (LD), although not with H2.…”

Tau gene promoter rs242557 and allele-specific protein binding

“…In our quest to investigate the functional basis of the risk conferred by the MAPT H1 haplotype with PSP and CBD, we identified, H1c, a sub-haplotype of H1 that drives this risk and therefore probably contains polymorphism(s) that have a functional effect on MAPT gene function [5,12] Our work however, implicates the MAPT promoter and the rs242557 SNP in particular and we have failed to identify any H1c-specific SNPs that would explain the effects on splicing of exon 10 to produce elevated levels of exon 10+ mRNA coding for the four-repeat tau (4R-tau) in particular [12]. Separate work by Rademakers et al [24] and also the conditional analysis in the recent PSP GWAS [9] Table 4.…”

“…with risk of neurodegeneration, we analysed the underlying MAPT genetic variation in PSP and CBD cases and showed that H1c, a sub-haplotype of the H1 clade, drives the association of the H1 haplotype -in other words, the H1c sub-haplotype contains the functional polymorphism that modulates risk [5,6]. We also showed that the H1c sub-haplotype is associated with Alzheimer's disease (AD) [7].…”