Creating the Pick's disease International Consortium: Association study of MAPT H2 haplotype with risk of Pick's disease.

Rebecca R Valentino, William J Scotton, Shanu F Roemer, Tammaryn Lashley, Michael G Heckman, Maryam Shoai, Alejandro Martinez-Carrasco, Nicole Tamvaka, Ronald L Walton, Matthew C Baker, Hannah L Macpherson, Raquel Real, Alexandra I Soto-Beasley, Kin Mok, Tamas Revesz, Thomas T Warner, Zane Jaunmuktane, Bradley F Boeve, Elizabeth A Christopher, Michael DeTureRanjan Duara, Neill R Graff-Radford, Keith A Josephs, David S Knopman, Shunsuke Koga, Melissa E Murray, Kelly E Lyons, Rajesh Pahwa, Joseph E Parisi, Ronald C Petersen, Jennifer Whitwell, Lea T Grinberg, Bruce Miller, Athena Schlereth, William W Seeley, Salvatore Spina, Murray Grossman, David J Irwin, Edward B Lee, EunRan Suh, John Q Trojanowski, Vivianna M Van Deerlin, David A Wolk, Theresa R Connors, Patrick M Dooley, Matthew P Frosch, Derek H Oakley, Iban Aldecoa, Mircea Balasa, Ellen Gelpi, Sergi Borrego-Écija, Rosa Maria de Eugenio Huélamo, Jordi Gascon-Bayarri, Raquel Sánchez-Valle, Pilar Sanz-Cartagena, Gerard Piñol-Ripoll, Laura Molina-Porcel, Eileen H Bigio, Margaret E Flanagan, Tamar Gefen, Emily J Rogalski, Sandra Weintraub, Javier Redding-Ochoa, Koping Chang, Juan C Troncoso, Stefan Prokop, Kathy L Newell, Bernardino Ghetti, Matthew Jones, Anna Richardson, Andrew C Robinson, Federico Roncaroli, Julie Snowden, Kieren Allinson, Oliver Green, James B Rowe, Poonam Singh, Thomas G Beach, Geidy E Serrano, Xena E Flowers, James E Goldman, Allison C Heaps, Sandra P Leskinen, Andrew F Teich, Sandra E Black, Julia L Keith, Mario Masellis, Istvan Bodi, Andrew King, Safa-Al Sarraj, Claire Troakes, Glenda M Halliday, John R Hodges, Jillian J Kril, John B Kwok, Olivier Piguet, Marla Gearing, Thomas Arzberger, Sigrun Roeber, Johannes Attems, Christopher M Morris, Alan J Thomas, Bret M Evers, Charles L White, Naguib Mechawar, Anne A Sieben, Patrick P Cras, Bart B De Vil, Peter Paul P P De Deyn, Charles Duyckaerts, Isabelle Le Ber, Danielle Seihean, Sabrina Turbant-Leclere, Ian R MacKenzie, Catriona McLean, Matthew D Cykowski, John F Ervin, Shih-Hsiu J Wang, Caroline Graff, Inger Nennesmo, Rashed M Nagra, James Riehl, Gabor G Kovacs, Giorgio Giaccone, Benedetta Nacmias, Manuela Neumann, Lee-Cyn Ang, Elizabeth C Finger, Cornelis Blauwendraat, Mike A Nalls, Andrew B Singleton, Dan Vitale, Cristina Cunha, Agostinho Carvalho, Zbigniew K Wszolek, Huw R Morris, Rosa Rademakers, John A Hardy, Dennis W Dickson, Jonathan D Rohrer, Owen A Ross

Research output: Contribution to journalArticle


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.

FUNDING: See funding section.

Original languageEnglish
Publication statusPublished - 24 Apr 2023


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