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DOI 10.1101/2023.04.17.23288471

Медицинская библиотека · medRxiv : the preprint server for health sciences · 2023

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

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

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Аннотация

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.

Для цитирования: Valentino Rebecca R, Scotton William J, Roemer Shanu F, Lashley Tammaryn, Heckman Michael G, Shoai Maryam, Martinez-Carrasco Alejandro, Tamvaka Nicole, Walton Ronald L, Baker Matthew C, Macpherson Hannah L, Real Raquel, Soto-Beasley Alexandra I, Mok Kin, Revesz Tamas, Warner Thomas T, Jaunmuktane Zane, Boeve Bradley F, Christopher Elizabeth A, DeTure Michael, Duara Ranjan, Graff-Radford Neill R, Josephs Keith A, Knopman David S, Koga Shunsuke, Murray Melissa E, Lyons Kelly E, Pahwa Rajesh, Parisi Joseph E, Petersen Ronald C, Whitwell Jennifer, Grinberg Lea T, Miller Bruce, Schlereth Athena, Seeley William W, Spina Salvatore, Grossman Murray, Irwin David J, Lee Edward B, Suh EunRan, Trojanowski John Q, Van Deerlin Vivianna M, Wolk David A, Connors Theresa R, Dooley Patrick M, Frosch Matthew P, Oakley Derek H, Aldecoa Iban, Balasa Mircea, Gelpi Ellen, Borrego-Écija Sergi, de Eugenio Huélamo Rosa Maria, Gascon-Bayarri Jordi, Sánchez-Valle Raquel, Sanz-Cartagena Pilar, Piñol-Ripoll Gerard, Molina-Porcel Laura, Bigio Eileen H, Flanagan Margaret E, Gefen Tamar, Rogalski Emily J, Weintraub Sandra, Redding-Ochoa Javier, Chang Koping, Troncoso Juan C, Prokop Stefan, Newell Kathy L, Ghetti Bernardino, Jones Matthew, Richardson Anna, Robinson Andrew C, Roncaroli Federico, Snowden Julie, Allinson Kieren, Green Oliver, Rowe James B, Singh Poonam, Beach Thomas G, Serrano Geidy E, Flowers Xena E, Goldman James E, Heaps Allison C, Leskinen Sandra P, Teich Andrew F, Black Sandra E, Keith Julia L, Masellis Mario, Bodi Istvan, King Andrew, Sarraj Safa-Al, Troakes Claire, Halliday Glenda M, Hodges John R, Kril Jillian J, Kwok John B, Piguet Olivier, Gearing Marla, Arzberger Thomas, Roeber Sigrun, Attems Johannes, Morris Christopher M, Thomas Alan J, Evers Bret M, White Charles L, Mechawar Naguib, Sieben Anne A, Cras Patrick P, De Vil Bart B, De Deyn Peter Paul P P, Duyckaerts Charles, Le Ber Isabelle, Seihean Danielle, Turbant-Leclere Sabrina, MacKenzie Ian R, McLean Catriona, Cykowski Matthew D, Ervin John F, Wang Shih-Hsiu J, Graff Caroline, Nennesmo Inger, Nagra Rashed M, Riehl James, Kovacs Gabor G, Giaccone Giorgio, Nacmias Benedetta, Neumann Manuela, Ang Lee-Cyn, Finger Elizabeth C, Blauwendraat Cornelis, Nalls Mike A, Singleton Andrew B, Vitale Dan, Cunha Cristina, Carvalho Agostinho, Wszolek Zbigniew K, Morris Huw R, Rademakers Rosa, Hardy John A, Dickson Dennis W, Rohrer Jonathan D, Ross Owen A. Creating the Pick's disease International Consortium: Association study of MAPT H2 haplotype with risk of Pick's disease.. medRxiv : the preprint server for health sciences. 2023. DOI: 10.1101/2023.04.17.23288471.
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