Browsing by Author "Asmann, Yan"

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    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.
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    Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD
    (Springer, 2019-02-09) Pottier, Cyril; Ren, Yingxue; Perkerson, Ralph B.; Baker, Matt; Jenkins, Gregory D.; van Blitterswijk, Marka; DeJesus-Hernandez, Mariely; van Rooij, Jeroen G. J.; Murray, Melissa E.; Christopher, Elizabeth; McDonnell, Shannon K.; Fogarty, Zachary; Batzler, Anthony; Tian, Shulan; Vicente, Cristina T.; Matchett, Billie; Karydas, Anna M.; Hsiung, Ging-Yuek Robin; Seelaar, Harro; Mol, Merel O.; Finger, Elizabeth C.; Graff, Caroline; Öijerstedt, Linn; Neumann, Manuela; Heutink, Peter; Synofzik, Matthis; Matthis, Carlo; Prudlo, Johannes; Rizzu, Patrizia; Simon-Sanchez, Javier; Edbauer, Dieter; Roeber, Sigrun; Diehl-Schmid, Janine; Evers, Bret M.; King, Andrew; Mesulam, M. Marsel; Weintraub, Sandra; Geula, Changiz; Bieniek, Kevin F.; Petrucelli, Leonard; Ahern, Geoffrey L.; Reiman, Eric M.; Woodruff, Bryan K.; Caselli, Richard J.; Huey, Edward D.; Farlow, Martin R.; Grafman, Jordan; Mead, Simon; Grinberg, Lea T.; Spina, Salvatore; Grossman, Murray; Irwin, David J.; Lee, Edward B.; Suh, EunRan; Snowden, Julie; Mann, David; Ertekin-Taner, Nilufer; Uitti, Ryan J.; Wszolek, Zbigniew K.; Josephs, Keith A.; Parisi, Joseph E.; Knopman, David S.; Petersen, Ronald C.; Hodges, John R.; Piguet, Olivier; Geier, Ethan G.; Yokoyama, Jennifer S.; Rissman, Robert A.; Rogaeva, Ekaterina; Keith, Julia; Zinman, Lorne; Tartaglia, Maria Carmela; Cairns, Nigel J.; Cruchaga, Carlos; Ghetti, Bernardino; Kofler, Julia; Lopez, Oscar L.; Beach, Thomas G.; Arzberger, Thomas; Herms, Jochen; Honig, Lawrence S.; Vonsattel, Jean Paul; Halliday, Glenda M.; Kwok, John B.; White, Charles L.; Gearing, Marla; Glass, Jonathan; Rollinson, Sara; Pickering-Brown, Stuart; Rohrer, Jonathan D.; Trojanowski, John Q.; Van Deerlin, Vivianna; Bigio, Eileen H.; Troakes, Claire; Al-Sarraj, Safa; Asmann, Yan; Miller, Bruce L.; Graff-Radford, Neill R.; Boeve, Bradley F.; Seeley, William W.; Mackenzie, Ian R. A.; van Swieten, John C.; 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) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1,131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations in TBK1 (1.5%) and other known FTLD genes (1.4%) were rare, and the disease in 57.7% of FTLD-TDP patients was unexplained by the known FTLD genes. To unravel the contribution of common genetic factors to the FTLD-TDP etiology in these patients, we conducted a two-stage association study comprising the analysis of whole-genome sequencing data from 517 FTLD-TDP patients and 838 controls, followed by targeted genotyping of the most associated genomic loci in 119 additional FTLD-TDP patients and 1653 controls. We identified three genome-wide significant FTLD-TDP risk loci: one new locus at chromosome 7q36 within the DPP6 gene led by rs118113626 (pvalue=4.82e-08, OR=2.12), and two known loci: UNC13A, led by rs1297319 (pvalue=1.27e-08, OR=1.50) and HLA-DQA2 led by rs17219281 (pvalue=3.22e-08, OR=1.98). While HLA represents a locus previously implicated in clinical FTLD and related neurodegenerative disorders, the association signal in our study is independent from previously reported associations. Through inspection of our whole genome sequence data for genes with an excess of rare loss-of-function variants in FTLD-TDP patients (n≥3) as compared to controls (n=0), we further discovered a possible role for genes functioning within the TBK1-related immune pathway (e.g. DHX58, TRIM21, IRF7) in the genetic etiology of FTLD-TDP. Together, our study based on the largest cohort of unrelated FTLD-TDP patients assembled to date provides a comprehensive view of the genetic landscape of FTLD-TDP, nominates novel FTLD-TDP risk loci, and strongly implicates the immune pathway in FTLD-TDP pathogenesis.