MAPT H2 haplotype and risk of Pick's disease in the Pick's disease International Consortium: a genetic association study
Authors: 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, Elizabeth A Christopher, Michael DeTure, William W Seeley, Edward B Lee, Matthew P Frosch, Laura Molina-Porcel, Tamar Gefen, Javier Redding-Ochoa, Bernardino Ghetti, Andrew C Robinson, Christopher Kobylecki, James B Rowe, Thomas G Beach, Andrew F Teich, Julia L Keith, Istvan Bodi, Glenda M Halliday, Marla Gearing, Thomas Arzberger, Christopher M Morris, Charles L White, Naguib Mechawar, Susana Boluda, Ian R MacKenzie, Catriona McLean, Matthew D Cykowski, Shih-Hsiu J Wang, Caroline Graff, Rashed M Nagra, Gabor G Kovacs, Giorgio Giaccone, Manuela Neumann, Lee-Cyn Ang, Agostinho Carvalho, Huw R Morris, Rosa Rademakers, John A Hardy, Dennis W Dickson, Jonathan D Rohrer, Owen A Ross, Thomas T Warner, Zane Jaunmuktane, Bradley F Boeve, Ranjan Duara, Neill R Graff-Radford, Keith A Josephs, David S Knopman, Shunsuke Koga, Melissa E Murray, Kelly E Lyons, Rajesh Pahwa, Ronald C Petersen, Jennifer L Whitwell, Lea T Grinberg, Bruce Miller, Athena Schlereth, Salvatore Spina, Murray Grossman, David J Irwin, EunRan Suh, John Q Trojanowski, Vivianna M Van Deerlin, David A Wolk, Theresa R Connors, Patrick M Dooley, Derek H Oakley, Iban Aldecoa, Mircea Balasa, Ellen Gelpi, Sergi Borrego-Écija, Jordi Gascon-Bayarri, Raquel Sánchez-Valle, Pilar Sanz-Cartagena, Gerard Piñol-Ripoll, Eileen H Bigio, Margaret E Flanagan, Emily J Rogalski, Sandra Weintraub, Julie A Schneider, Lihua Peng, Xiongwei Zhu, Koping Chang, Juan C Troncoso, Stefan Prokop, Kathy L Newell, Matthew Jones, Anna Richardson, Federico Roncaroli, Julie Snowden, Kieren Allinson, Poonam Singh, Geidy E Serrano, Xena E Flowers, James E Goldman, Allison C Heaps, Sandra P Leskinen, Sandra E Black, Mario Masellis, Andrew King, Safa Al-Sarraj, Claire Troakes, John R Hodges, Jillian J Kril, John B Kwok, Olivier Piguet, Sigrun Roeber, Johannes Attems, Alan J Thomas, Bret M. Evers, Kevin F Bieniek, Anne A Sieben, Patrick P Cras, Bart B De Vil, Thomas Bird, Rudolph J Castellani, Ann Chaffee, Erin Franklin, Vahram Haroutunian, Max Jacobsen, Dirk Keene, Caitlin S Latimer, Jeff Metcalf, Richard J Perrin, Dushyant P Purohit, Robert A Rissman, Aimee Schantz, Jamie Walker, Peter P De Deyn, Charles Duyckaerts, Isabelle Le Ber, Danielle Seilhean, Sabrina Turbant-Leclere, John F Ervin, Inger Nennesmo, James Riehl, Benedetta Nacmias, Elizabeth C Finger, Cornelis Blauwendraat, Mike A Nalls, Andrew B Singleton, Dan Vitale, Cristina Cunha, Zbigniew K Wszolek
Journal: The Lancet Neurology (2024)

BackgroundPick's disease is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. Pick's disease is pathologically defined by the presence in the frontal and temporal lobes of Pick bodies, composed of hyperphosphorylated, three-repeat tau protein, encoded by the MAPT gene. MAPT has two distinct haplotypes, H1 and H2; the MAPT H1 haplotype is the major genetic risk factor for four-repeat tauopathies (eg, progressive supranuclear palsy and corticobasal degeneration), and the MAPT H2 haplotype is protective for these disorders. The primary aim of this study was to evaluate the association of MAPT H2 with Pick's disease risk, age at onset, and disease duration.MethodsIn this genetic association study, we used data from the Pick's disease International Consortium, which we established to enable collection of data from individuals with pathologically confirmed Pick's disease worldwide. For this analysis, we collected brain samples from individuals with pathologically confirmed Pick's disease from 35 sites (brainbanks and hospitals) in North America, Europe, and Australia between Jan 1, 2020, and Jan 31, 2023. Neurologically healthy controls were recruited from the Mayo Clinic (FL, USA, or MN, USA between March 1, 1998, and Sept 1, 2019). For the primary analysis, individuals were directly genotyped for the MAPT H1-H2 haplotype-defining variant rs8070723. In a secondary analysis, we genotyped and constructed the six-variant-defined (rs1467967-rs242557-rs3785883-rs2471738-rs8070723-rs7521) MAPT H1 subhaplotypes. Associations of MAPT variants and MAPT haplotypes with Pick's disease risk, age at onset, and disease duration were examined using logistic and linear regression models; odds ratios (ORs) and β coefficients were estimated and correspond to each additional minor allele or each additional copy of the given haplotype.FindingsWe obtained brain samples from 338 people with pathologically confirmed Pick's disease (205 [61%] male and 133 [39%] female; 338 [100%] White) and 1312 neurologically healthy controls (611 [47%] male and 701 [53%] female; 1312 [100%] White). The MAPT H2 haplotype was associated with increased risk of Pick's disease compared with the H1 haplotype (OR 1·35 [95% CI 1·12 to 1·64], p=0·0021). MAPT H2 was not associated with age at onset (β –0·54 [95% CI –1·94 to 0·87], p=0·45) or disease duration (β 0·05 [–0·06 to 0·16], p=0·35). Although not significant after correcting for multiple testing, associations were observed at p less than 0·05: with risk of Pick's disease for the H1f subhaplotype (OR 0·11 [0·01 to 0·99], p=0·049); with age at onset for H1b (β 2·66 [0·63 to 4·70], p=0·011), H1i (β –3·66 [–6·83 to –0·48], p=0·025), and H1u (β –5·25 [–10·42 to –0·07], p=0·048); and with disease duration for H1x (β –0·57 [–1·07 to –0·07], p=0·026).InterpretationThe Pick's disease International Consortium provides an opportunity to do large studies to enhance our understanding of the pathobiology of Pick's disease. This study shows that, in contrast to the decreased risk of four-repeat tauopathies, the MAPT H2 haplotype is associated with an increased risk of Pick's disease in people of European ancestry. This finding could inform development of isoform-related therapeutics for tauopathies.FundingWellcome Trust, Rotha Abraham Trust, Brain Research UK, the Dolby Fund, Dementia Research Institute (Medical Research Council), US National Institutes of Health, and the Mayo Clinic Foundation.