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

Abstract

In addition to senile plaques, neurofibrillary tangles are characteristic of Alzheimer's disease (AD) pathology, suggesting a clear involvement of the microtubule-associated protein tau (MAPT) in AD. Recent findings, suggesting that the H1c haplotype is associated with increased risk, now also implicate MAPT genetically. In this study, we aim to clarify this association by a fine mapping approach using both a traditional phenotypic association analysis and a quantitative trait (QT) analysis using cerebrospinal fluid (CSF) tau protein levels in the German population. Here, we report that both methodologies identify that the H1c haplotype may play important role in AD (AD risk, P = 0.007, uncorrected; CSF tau levels, P = 0.027, uncorrected). Further, the use of a sliding window approach in the QT analysis allowed for the narrowing down of the region where a probable causal variant may be located. The data suggest that this may lie at or within close proximity to the rs242557 single nucleotide polymorphism as association with CSF tau levels seems to be primarily driven by rs242557 in a gene dosagedependent manner (trend model: P = 0.002, uncorrected). These findings provide functional evidence to support the genetic association of MAPT with AD.

Examination of the current top candidate genes for AD in a genome-wide association study

“…Six genes investigated in our study fell into the first category and of these, only MAPT and SORL1 showed a nominally significant association in the immediate gene region. Our GWAS did not allow delineation of MAPT H1 and H2 haplotypes, as was the case in previous studies, 42,45 but the strong disease association of rs1467967 noted here falls into the H1c haplotype that appears to drive the association. Likewise, the strong haplotype-based signal found in the GWAS was localised in the region that delineates H1/H2 MAPT haplotypes.…”

“…Both haplotypes can be tagged by six markers, [40][41][42] but only three of these SNPs, rs1467967, rs242557 and rs3785883, were genotyped in our GWAS. A total of 25 SNPs in the gene region were analysed, 20 of which were located within MAPT itself.…”

H1 tau haplotype-related genomic variation at 17q21.3 as an Asian heritage of the European Gypsy population

“…H1 carriers are under a negative selection, as H2 carrier women have more children (Stefansson et al, 2005;Voight et al, 2006) and because of the possible role of H1 allele in tauopathies. Alzheimer's disease Laws et al, 2007), Parkinson's disease (Skipper et al, 2004), progressive supranuclear palsy , argyrophilic grain disease (Fujino et al, 2005), corticobasal degeneration (Buee and Delacourte, 1999) and the Parkinson-dementia complex of Guam (Sundar et al, 2007) are all associated with MAPT H1. In addition, it seems that, besides carrying H1 allele, there are other factors that influence disease onset.…”

“…These extensive investigations have revealed that two main nonrecombining MAPT locus haplotypes (H1 and H2) can be distinguished. The H1 haplotype and/or subhaplotypes play a general role in the development of sporadic tauopathies (Laws et al, 2007;Myers et al, 2007). It has also become obvious that there are notable differences in the geographical distribution of the MAPT-related haplotypes.…”

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

“…The extensive investigations revealed that out of the two main non-recombining MAPT locus haplotypes H1 plays a role in the development of sporadic tauopathies (Laws et al, 2007) while H2 is involved in a neurodevelopmental disorder.…”