Lei Yu1, Philip L De Jager1, Jingyun Yang1, John Q Trojanowski1, David A Bennett1, Julie A Schneider2. 1. From the Rush Alzheimer's Disease Center (L.Y., J.Y., D.A.B., J.A.S.), the Department of Neurological Sciences (L.Y., J.Y., D.A.B., J.A.S.), and the Department of Pathology (J.A.S.), Rush University Medical Center, Chicago, IL; Program in Translational NeuroPsychiatric Genomics (P.L.D.), Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston; Harvard Medical School (P.L.D.), Boston; Program in Medical and Population Genetics, Broad Institute (P.L.D.), Cambridge, MA; and the Department of Pathology and Laboratory Medicine (J.Q.T.), Institute on Aging, Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia. 2. From the Rush Alzheimer's Disease Center (L.Y., J.Y., D.A.B., J.A.S.), the Department of Neurological Sciences (L.Y., J.Y., D.A.B., J.A.S.), and the Department of Pathology (J.A.S.), Rush University Medical Center, Chicago, IL; Program in Translational NeuroPsychiatric Genomics (P.L.D.), Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston; Harvard Medical School (P.L.D.), Boston; Program in Medical and Population Genetics, Broad Institute (P.L.D.), Cambridge, MA; and the Department of Pathology and Laboratory Medicine (J.Q.T.), Institute on Aging, Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia. julie_a_schneider@rush.edu.
Abstract
OBJECTIVE: To determine the independent association of the TMEM106B variants with transactive response DNA binding protein 43 (TDP-43) pathology in older persons without frontotemporal lobar degeneration (FTLD) and to explore functional pathways that link the risk variants to the pathology, including a GRN mRNA pathway. METHODS: Data came from 544 autopsied participants without FTLD in 2 community-based studies of aging. Participants underwent uniform neuropathologic evaluations, including TDP-43 cytoplasmic inclusions. We examined the association of TMEM106B variants with a semiquantitative measure of TDP-43 pathology in a series of regression analysis. We explored potential pathways by leveraging genetic, brain DNA methylation, miRNA, and transcriptomic data collected from this same group of participants. RESULTS: TDP-43 pathology was identified in 51.7% of the participants. The index single-nucleotide polymorphism (SNP), rs1990622(A), was associated with more advanced TDP-43 pathology. Top hits from fine mapping of the locus were in linkage disequilibrium of the index SNP. The association remained significant after adjustment for other neuropathologies including Alzheimer disease and hippocampal sclerosis (odds ratio = 1.351, 95% confidence interval = 1.068-1.709, p = 0.012). GRN expression was upregulated in rs1990622(AA/AG) carriers, and was associated with more advanced TDP-43 pathology. The TMEM106B variants were associated with lower level of DNA methylation in an active enhancer in GRN. CONCLUSIONS: Common variants in TMEM106B serve as a distinct risk factor for TDP-43 pathology in older persons without FTLD. The role of GRN expression and epigenetic mechanisms associating TMEM106B in the accumulation of TDP-43 in older persons require further study.
OBJECTIVE: To determine the independent association of the TMEM106B variants with transactive response DNA binding protein 43 (TDP-43) pathology in older persons without frontotemporal lobar degeneration (FTLD) and to explore functional pathways that link the risk variants to the pathology, including a GRN mRNA pathway. METHODS: Data came from 544 autopsied participants without FTLD in 2 community-based studies of aging. Participants underwent uniform neuropathologic evaluations, including TDP-43 cytoplasmic inclusions. We examined the association of TMEM106B variants with a semiquantitative measure of TDP-43 pathology in a series of regression analysis. We explored potential pathways by leveraging genetic, brain DNA methylation, miRNA, and transcriptomic data collected from this same group of participants. RESULTS:TDP-43 pathology was identified in 51.7% of the participants. The index single-nucleotide polymorphism (SNP), rs1990622(A), was associated with more advanced TDP-43 pathology. Top hits from fine mapping of the locus were in linkage disequilibrium of the index SNP. The association remained significant after adjustment for other neuropathologies including Alzheimer disease and hippocampal sclerosis (odds ratio = 1.351, 95% confidence interval = 1.068-1.709, p = 0.012). GRN expression was upregulated in rs1990622(AA/AG) carriers, and was associated with more advanced TDP-43 pathology. The TMEM106B variants were associated with lower level of DNA methylation in an active enhancer in GRN. CONCLUSIONS: Common variants in TMEM106B serve as a distinct risk factor for TDP-43 pathology in older persons without FTLD. The role of GRN expression and epigenetic mechanisms associating TMEM106B in the accumulation of TDP-43 in older persons require further study.
Authors: Nicola J Rutherford; Minerva M Carrasquillo; Ma Li; Gina Bisceglio; Joshua Menke; Keith A Josephs; Joseph E Parisi; Ronald C Petersen; Neill R Graff-Radford; Steven G Younkin; Dennis W Dickson; Rosa Rademakers Journal: Neurology Date: 2012-08-01 Impact factor: 9.910
Authors: David A Bennett; Julie A Schneider; Aron S Buchman; Lisa L Barnes; Patricia A Boyle; Robert S Wilson Journal: Curr Alzheimer Res Date: 2012-07 Impact factor: 3.498
Authors: N Finch; M M Carrasquillo; M Baker; N J Rutherford; G Coppola; M Dejesus-Hernandez; R Crook; T Hunter; R Ghidoni; L Benussi; J Crook; E Finger; K J Hantanpaa; A M Karydas; P Sengdy; J Gonzalez; W W Seeley; N Johnson; T G Beach; M Mesulam; G Forloni; A Kertesz; D S Knopman; R Uitti; C L White; R Caselli; C Lippa; E H Bigio; Z K Wszolek; G Binetti; I R Mackenzie; B L Miller; B F Boeve; S G Younkin; D W Dickson; R C Petersen; N R Graff-Radford; D H Geschwind; R Rademakers Journal: Neurology Date: 2010-12-22 Impact factor: 9.910
Authors: Alice S Chen-Plotkin; Travis L Unger; Michael D Gallagher; Emily Bill; Linda K Kwong; Laura Volpicelli-Daley; Johanna I Busch; Sebastian Akle; Murray Grossman; Vivianna Van Deerlin; John Q Trojanowski; Virginia M-Y Lee Journal: J Neurosci Date: 2012-08-15 Impact factor: 6.167
Authors: Alexandra M Nicholson; Nicole A Finch; Aleksandra Wojtas; Matt C Baker; Ralph B Perkerson; Monica Castanedes-Casey; Linda Rousseau; Luisa Benussi; Giuliano Binetti; Roberta Ghidoni; Ging-Yuek R Hsiung; Ian R Mackenzie; Elizabeth Finger; Bradley F Boeve; Nilüfer Ertekin-Taner; Neill R Graff-Radford; Dennis W Dickson; Rosa Rademakers Journal: J Neurochem Date: 2013-07-01 Impact factor: 5.372
Authors: Nigel J Cairns; Eileen H Bigio; Ian R A Mackenzie; Manuela Neumann; Virginia M-Y Lee; Kimmo J Hatanpaa; Charles L White; Julie A Schneider; Lea Tenenholz Grinberg; Glenda Halliday; Charles Duyckaerts; James S Lowe; Ida E Holm; Markus Tolnay; Koichi Okamoto; Hideaki Yokoo; Shigeo Murayama; John Woulfe; David G Munoz; Dennis W Dickson; Paul G Ince; John Q Trojanowski; David M A Mann Journal: Acta Neuropathol Date: 2007-06-20 Impact factor: 17.088
Authors: Robert S Wilson; Lei Yu; John Q Trojanowski; Er-Yun Chen; Patricia A Boyle; David A Bennett; Julie A Schneider Journal: JAMA Neurol Date: 2013-11 Impact factor: 18.302
Authors: Peter T Nelson; Gregory A Jicha; Wang-Xia Wang; Eseosa Ighodaro; Sergey Artiushin; Colin G Nichols; David W Fardo Journal: Ageing Res Rev Date: 2015-07-28 Impact factor: 10.895
Authors: Dennis W Dickson; Rosa Rademakers; Alexandra M Nicholson; Julie A Schneider; Lei Yu; David A Bennett Journal: Neurology Date: 2015-10-13 Impact factor: 9.910
Authors: Hyun-Sik Yang; Charles C White; Hans-Ulrich Klein; Lei Yu; Christopher Gaiteri; Yiyi Ma; Daniel Felsky; Sara Mostafavi; Vladislav A Petyuk; Reisa A Sperling; Nilüfer Ertekin-Taner; Julie A Schneider; David A Bennett; Philip L De Jager Journal: Neuron Date: 2020-06-10 Impact factor: 17.173
Authors: Shunsuke Koga; Naomi Kouri; Ronald L Walton; Mark T W Ebbert; Keith A Josephs; Irene Litvan; Neill Graff-Radford; J Eric Ahlskog; Ryan J Uitti; Jay A van Gerpen; Bradley F Boeve; Adam Parks; Owen A Ross; Dennis W Dickson Journal: Acta Neuropathol Date: 2018-06-20 Impact factor: 17.088
Authors: Kevin F Bieniek; Owen A Ross; Kerry A Cormier; Ronald L Walton; Alexandra Soto-Ortolaza; Amelia E Johnston; Pamela DeSaro; Kevin B Boylan; Neill R Graff-Radford; Zbigniew K Wszolek; Rosa Rademakers; Bradley F Boeve; Ann C McKee; Dennis W Dickson Journal: Acta Neuropathol Date: 2015-10-30 Impact factor: 17.088
Authors: Thomas F Tropea; Jordan Mak; Michael H Guo; Sharon X Xie; Eunran Suh; Jacqueline Rick; Andrew Siderowf; Daniel Weintraub; Murray Grossman; David Irwin; David A Wolk; John Q Trojanowski; Vivianna Van Deerlin; Alice S Chen-Plotkin Journal: Ann Neurol Date: 2019-06 Impact factor: 10.422
Authors: Konstantinos Arfanakis; Arnold M Evia; Sue E Leurgans; Luis F C Cardoso; Arman Kulkarni; Nabil Alqam; Lucas F Lopes; Diego Vieira; David A Bennett; Julie A Schneider Journal: J Alzheimers Dis Date: 2020 Impact factor: 4.472
Authors: Bryan D James; Robert S Wilson; Patricia A Boyle; John Q Trojanowski; David A Bennett; Julie A Schneider Journal: Brain Date: 2016-11-01 Impact factor: 13.501
Authors: Lei Yu; Vladislav A Petyuk; Chris Gaiteri; Sara Mostafavi; Tracy Young-Pearse; Raj C Shah; Aron S Buchman; Julie A Schneider; Paul D Piehowski; Ryan L Sontag; Thomas L Fillmore; Tujin Shi; Richard D Smith; Philip L De Jager; David A Bennett Journal: Ann Neurol Date: 2018-07-03 Impact factor: 10.422