MAPT H2 haplotype and risk of Pick's disease in the Pick's disease International Consortium: a genetic association study.

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

doi:10.1016/S1474-4422(24)00083-8

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000269189 1001_ $$aValentino, Rebecca R$$b0
000269189 245__ $$aMAPT H2 haplotype and risk of Pick's disease in the Pick's disease International Consortium: a genetic association study.
000269189 260__ $$aLondon$$bLancet Publ. Group$$c2024
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000269189 520__ $$aPick'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.In 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.We 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).The 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.Wellcome 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.
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000269189 650_2 $$2MeSH$$aFemale
000269189 650_2 $$2MeSH$$aHumans
000269189 650_2 $$2MeSH$$aMale
000269189 650_2 $$2MeSH$$aGenetic Association Studies
000269189 650_2 $$2MeSH$$aHaplotypes
000269189 650_2 $$2MeSH$$aPick Disease of the Brain: genetics
000269189 650_2 $$2MeSH$$atau Proteins: genetics
000269189 650_2 $$2MeSH$$aTauopathies
000269189 650_7 $$2NLM Chemicals$$aMAPT protein, human
000269189 7001_ $$aScotton, William J$$b1
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000269189 7001_ $$aGearing, Marla$$b32
000269189 7001_ $$0P:(DE-2719)2811333$$aArzberger, Thomas$$b33$$udzne
000269189 7001_ $$aMorris, Christopher M$$b34
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000269189 7001_ $$aMechawar, Naguib$$b36
000269189 7001_ $$aBoluda, Susana$$b37
000269189 7001_ $$0P:(DE-2719)9000939$$aMacKenzie, Ian R$$b38
000269189 7001_ $$aMcLean, Catriona$$b39
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000269189 7001_ $$aKovacs, Gabor G$$b44
000269189 7001_ $$aGiaccone, Giorgio$$b45
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000269189 7001_ $$aConsortium, Pick's disease International$$b55$$eCollaboration Author
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