Creating the Pick's disease International Consortium: Association study of MAPT H2 haplotype with risk of Pick's
Rebecca R Valentino1, William J Scotton2, Shanu F Roemer1
1Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Background:
Pick's disease (PiD) is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. PiD is pathologically defined by argyrophilic inclusion Pick bodies and ballooned neurons in the frontal and temporal brain lobes. PiD is characterised by the presence of Pick bodies which are formed from aggregated, hyperphosphorylated, 3-repeat tau proteins, encoded by the MAPT gene. The MAPT H2 haplotype has consistently been associated with a decreased disease risk of the 4-repeat tauopathies of progressive supranuclear palsy and corticobasal degeneration, however its role in susceptibility to PiD is unclear. The primary aim of this study was to evaluate the association between MAPT H2 and risk of PiD.
Methods:
We established the Pick's disease International Consortium (PIC) and collected 338 (60.7% male) pathologically confirmed PiD brains from 39 sites worldwide. 1,312 neurologically healthy clinical controls were recruited from Mayo Clinic Jacksonville, FL (N=881) or Rochester, MN (N=431). For the primary analysis, subjects were directly genotyped for MAPT H1-H2 haplotype-defining variant rs8070723. In secondary analysis, we genotyped and constructed the six-variant MAPT H1 subhaplotypes (rs1467967, rs242557, rs3785883, rs2471738, rs8070723, and rs7521).
Findings:
Our primary analysis found that the MAPT H2 haplotype was associated with increased risk of PiD (OR: 1.35, 95% CI: 1.12-1.64 P=0.002). In secondary analysis involving H1 subhaplotypes, a protective association with PiD was observed for the H1f haplotype (0.0% vs. 1.2%, P=0.049), with a similar trend noted for H1b (OR: 0.76, 95% CI: 0.58-1.00, P=0.051). The 4-repeat tauopathy risk haplotype MAPT H1c was not associated with PiD susceptibility (OR: 0.93, 95% CI: 0.70-1.25, P=0.65).
Interpretation:
The PIC represents the first opportunity to perform relatively large-scale studies to enhance our understanding of the pathobiology of PiD. This study demonstrates that in contrast to its protective role in 4R tauopathies, the MAPT H2 haplotype is associated with an increased risk of PiD. This finding is critical in directing isoform-related therapeutics for tauopathies.
Insights
The MAPT H2 haplotype increases Pick's disease risk, unlike its protective effect in other tauopathies. This finding is crucial for developing targeted tauopathy therapeutics.
Area of Science:
- Neuroscience
- Genetics
- Pathology
Background:
- Pick's disease (PiD) is a rare frontotemporal dementia and primary tauopathy.
- Pathologically defined by Pick bodies and ballooned neurons.
- The role of the MAPT H2 haplotype in PiD susceptibility was previously unclear.
Approach:
- Established the Pick's disease International Consortium (PIC) with 338 PiD brains and 1,312 controls.
- Genotyped the MAPT H1-H2 haplotype-defining variant rs8070723 for primary analysis.
- Conducted secondary analysis using six MAPT H1 subhaplotypes.
Key Points:
- The MAPT H2 haplotype was associated with an increased risk of PiD (OR: 1.35, P=0.002).
- The MAPT H1f subhaplotype showed a protective association with PiD (P=0.049).
- The MAPT H1c subhaplotype was not associated with PiD susceptibility (P=0.65).
Conclusions:
- The MAPT H2 haplotype increases PiD risk, contrasting its protective role in 4R tauopathies.
- This study provides the first large-scale investigation into MAPT haplotypes and PiD.
- Findings are critical for directing isoform-specific tauopathy therapeutics.
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