Novel haplotypes in 17q21 are associated with progressive supranuclear palsy

Abstract

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are sporadic neurodegenerative diseases presenting as atypical parkinsonian disorders, characterized by the presence of tau-positive neurofibrillary tangles. Recently, an extended haplotype (H1E) of 787.6 kb that comprises several genes including MAPT showed increased association with PSP. The objective of this study was to determine the size of the H1E haplotype associated with PSP and CBD in different populations and to identify specific subhaplotypes in the background of H1E haplotype. Nineteen single nucleotide polymorphisms (SNPs) in the 17q21 region were genotyped in two case-control samples. The SNPs that were associated with higher risk for the disease in the homozygous state delimit a region of more that 1 Mb. Haplotype analyses in the Spanish sample showed that the most frequent haplotype found among the patients (H1E'), which extends 1.04 Mb and contains several genes such as MAPT, CRHR1, IMP5, Saitohin, WTN3, and NSF. A specific subhaplotype (H1E'A) was present in 16% of PSP patients but was not observed in the controls. Furthermore, the H2E'A haplotype, was rarely present in the disease group suggesting that it plays a protective role. The identification of these specific subhaplotypes that modify risk for PSP/CBD supports the hypothesis that a pathogenic allele exists in a subgroup of PSP patients.

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

“…[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. 12,[17][18][19] This diversity can be tagged through five single-nucleotide polymorphisms (SNPs) and the aforementioned delIn9. 13,16 The H1c variant of this haplotype is reported to be the predominant cause of the H1 association with progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) 17,20,21 and more recently has been associated with AD.…”

“…12,[17][18][19] This diversity can be tagged through five single-nucleotide polymorphisms (SNPs) and the aforementioned delIn9. 13,16 The H1c variant of this haplotype is reported to be the predominant cause of the H1 association with progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) 17,20,21 and more recently has been associated with AD. 16 Prior studies of MAPT associations with AD had produced inconclusive findings; 14,15,[22][23][24][25] however, the study of Myers et al 16 was the first study to assess the impact of this H1 diversity.…”

Association of Tau Haplotype-Tagging Polymorphisms with Parkinson’s Disease in Diverse Ethnic Parkinson’s Disease Cohorts

“…The most frequent haplotype H1 was reported to regulate transcription of MAPT and associated with tauopathies [6,9] . Further studies have shown that a subhaplotype of H1 (H1c) is largely responsible for the association between the haplotype H1 and the sporadic tauopathies [10][11][12] .…”

Progress in the genetics of progressive supranuclear palsy: Tau gene and beyond

“…Accordingly, several polymorphic sites, which tag the diversity between the H1 and the H2 haplotypes, segregate together, or in genetic terms are in linkage disequilibrium (LD). Several studies have consistently shown that the H1 haplotype (the more common in humans) is strongly associated, whereas the H2 haplotype is underrepresented in PSP patients [7,8], suggesting that H1 predisposes to or that H2 protects from PSP, or both.…”