Browsing by Author "Gefen, Tamar"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Creating the Pick's disease International Consortium: Association study of MAPT H2 haplotype with risk of Pick's disease
    (medRxiv, 2023-04-24) 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.; Pathology and Laboratory Medicine, School of Medicine
    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.
  • Thumbnail Image
    Item
    Deciphering distinct genetic risk factors for FTLD-TDP pathological subtypes via whole-genome sequencing
    (Springer Nature, 2025-04-25) Pottier, Cyril; Küçükali, Fahri; Baker, Matt; Batzler, Anthony; Jenkins, Gregory D.; van Blitterswijk, Marka; Vicente, Cristina T.; De Coster, Wouter; Wynants, Sarah; Van de Walle, Pieter; Ross, Owen A.; Murray, Melissa E.; Faura, Júlia; Haggarty, Stephen J.; van Rooij, Jeroen G. J.; Mol, Merel O.; Hsiung, Ging-Yuek R.; Graff, Caroline; Öijerstedt, Linn; Neumann, Manuela; Asmann, Yan; McDonnell, Shannon K.; Baheti, Saurabh; Josephs, Keith A.; Whitwell, Jennifer L.; Bieniek, Kevin F.; Forsberg, Leah; Heuer, Hilary; Lago, Argentina Lario; Geier, Ethan G.; Yokoyama, Jennifer S.; Oddi, Alexis P.; Flanagan, Margaret; Mao, Qinwen; Hodges, John R.; Kwok, John B.; Domoto-Reilly, Kimiko; Synofzik, Matthis; Wilke, Carlo; Onyike, Chiadi; Dickerson, Bradford C.; Evers, Bret M.; Dugger, Brittany N.; Munoz, David G.; Keith, Julia; Zinman, Lorne; Rogaeva, Ekaterina; Suh, EunRan; Gefen, Tamar; Geula, Changiz; Weintraub, Sandra; Diehl-Schmid, Janine; Farlow, Martin R.; Edbauer, Dieter; Woodruff, Bryan K.; Caselli, Richard J.; Donker Kaat, Laura L.; Huey, Edward D.; Reiman, Eric M.; Mead, Simon; King, Andrew; Roeber, Sigrun; Nana, Alissa L.; Ertekin-Taner, Nilufer; Knopman, David S.; Petersen, Ronald C.; Petrucelli, Leonard; Uitti, Ryan J.; Wszolek, Zbigniew K.; Ramos, Eliana Marisa; Grinberg, Lea T.; Gorno Tempini, Maria Luisa; Rosen, Howard J.; Spina, Salvatore; Piguet, Olivier; Grossman, Murray; Trojanowski, John Q.; Keene, C. Dirk; Jin, Lee-Way; Prudlo, Johannes; Geschwind, Daniel H.; Rissman, Robert A.; Cruchaga, Carlos; Ghetti, Bernardino; Halliday, Glenda M.; Beach, Thomas G.; Serrano, Geidy E.; Arzberger, Thomas; Herms, Jochen; Boxer, Adam L.; Honig, Lawrence S.; Vonsattel, Jean P.; Lopez, Oscar L.; Kofler, Julia; White, Charles L., III; Gearing, Marla; Glass, Jonathan; Rohrer, Jonathan D.; Irwin, David J.; Lee, Edward B.; Van Deerlin, Vivianna; Castellani, Rudolph; Mesulam, Marsel M.; Tartaglia, Maria C.; Finger, Elizabeth C.; Troakes, Claire; Al-Sarraj, Safa; Dalgard, Clifton L.; Miller, Bruce L.; Seelaar, Harro; Graff-Radford, Neill R.; Boeve, Bradley F.; Mackenzie, Ian Ra; van Swieten, John C.; Seeley, William W.; Sleegers, Kristel; Dickson, Dennis W.; Biernacka, Joanna M.; Rademakers, Rosa; Neurology, School of Medicine
    Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) is a fatal neurodegenerative disorder with only a limited number of risk loci identified. We report our comprehensive genome-wide association study as part of the International FTLD-TDP Whole-Genome Sequencing Consortium, including 985 patients and 3,153 controls compiled from 26 institutions/brain banks in North America, Europe and Australia, and meta-analysis with the Dementia-seq cohort. We confirm UNC13A as the strongest overall FTLD-TDP risk factor and identify TNIP1 as a novel FTLD-TDP risk factor. In subgroup analyzes, we further identify genome-wide significant loci specific to each of the three main FTLD-TDP pathological subtypes (A, B and C), as well as enrichment of risk loci in distinct tissues, brain regions, and neuronal subtypes, suggesting distinct disease aetiologies in each of the subtypes. Rare variant analysis confirmed TBK1 and identified C3AR1, SMG8, VIPR1, RBPJL, L3MBTL1 and ANO9, as novel subtype-specific FTLD-TDP risk genes, further highlighting the role of innate and adaptive immunity and notch signaling pathway in FTLD-TDP, with potential diagnostic and novel therapeutic implications.