title: The TMEM106B locus and TDP-43 pathology in older persons without FTLD.
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.
authors: 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.
authors: Lei
authors: L
authors: Yu
authors: 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.
authors: Philip L
authors: PL
authors: De Jager
authors: 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.
authors: Jingyun
authors: J
authors: Yang
authors: 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.
authors: John Q
authors: JQ
authors: Trojanowski
authors: 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.
authors: David A
authors: DA
authors: Bennett
authors: 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.
authors: Julie A
authors: JA
authors: Schneider
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics* / Q000473:pathology; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D057174:Frontotemporal Lobar Degeneration; D056426:Genetic Loci / Q000235:genetics*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D057177:TDP-43 Proteinopathies / Q000175:diagnosis / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C556915:TMEM106B protein, human
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