title: Genome-wide association study identifiesMAPTlocus influencing human plasma tau levels.
abstract: OBJECTIVE
  To identify genetic loci associated with plasma tau concentrations in healthy elders and individuals with Alzheimer disease.
  
  
  METHODS
  Four hundred sixty-three non-Hispanic white individuals exceeding quality control criteria were included from the Alzheimer's Disease Neuroimaging Initiative (ADNI-1) cohort. Association of plasma tau with genetic polymorphisms was performed with a linear regression model. Significant associations were validated in an independent replication cohort consisting of 431 healthy elders or individuals with mild cognitive impairment recruited from the University of California, San Francisco Memory and Aging Center.
  
  
  RESULTS
  The minor allele (A) of rs242557 in the microtubule-associated protein tau gene (MAPT) was associated with higher plasma tau levels at genome-wide significance (p= 4.85 × 10-9, empiric family-wise error correctedp= 0.0024) in a dose-dependent fashion. This association was also observed in the replication cohort (p= 1.0 × 10-5; joint analysisp= 1.2 × 10-12). Single nucleotide polymorphisms nearPARK2(rs2187213) (p= 6.15 × 10-6),IL2RA(rs7072793, rs7073236) (p= 7.89 × 10-6), and an intergenic locus on 9p21.3 (rs7047280) (p= 8.13 × 10-6) were identified as suggestive loci associated with plasma tau levels.
  
  
  CONCLUSIONS
  MAPTH1c haplotype (rs242557) has previously been identified as a genetic risk factor for progressive supranuclear palsy and corticobasal degeneration. The current findings suggest that plasma tau concentration could be an endophenotype for identifying risk for 4-repeat tauopathies in older individuals.
authors.affiliation: From the Department of Neurology (J.C., K.W., G.C.), David Geffen School of Medicine, and Memory and Aging Center (J.S.Y., J.H.K., H.R., B.L.M., A.L.B.), Department of Neurology, University of California, Los Angeles; Department of Neurology (J.-T.Y., H.-F.W.), Qingdao Municipal Hospital, Nanjing Medical University, China; Clinical Neurochemistry Laboratory (H.Z., K.B.), Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg Mölndal, Sweden; Department of Molecular Neuroscience (H.Z.), UCL Institute of Neurology, London, UK; and Center for Imaging of Neurodegenerative Diseases (M.W.W.), VAMC San Francisco, CA.
authors.forename: Jason
authors.initials: J
authors.lastname: Chen
authors.affiliation: From the Department of Neurology (J.C., K.W., G.C.), David Geffen School of Medicine, and Memory and Aging Center (J.S.Y., J.H.K., H.R., B.L.M., A.L.B.), Department of Neurology, University of California, Los Angeles; Department of Neurology (J.-T.Y., H.-F.W.), Qingdao Municipal Hospital, Nanjing Medical University, China; Clinical Neurochemistry Laboratory (H.Z., K.B.), Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg Mölndal, Sweden; Department of Molecular Neuroscience (H.Z.), UCL Institute of Neurology, London, UK; and Center for Imaging of Neurodegenerative Diseases (M.W.W.), VAMC San Francisco, CA.
authors.forename: Jin-Tai
authors.initials: JT
authors.lastname: Yu
authors.affiliation: From the Department of Neurology (J.C., K.W., G.C.), David Geffen School of Medicine, and Memory and Aging Center (J.S.Y., J.H.K., H.R., B.L.M., A.L.B.), Department of Neurology, University of California, Los Angeles; Department of Neurology (J.-T.Y., H.-F.W.), Qingdao Municipal Hospital, Nanjing Medical University, China; Clinical Neurochemistry Laboratory (H.Z., K.B.), Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg Mölndal, Sweden; Department of Molecular Neuroscience (H.Z.), UCL Institute of Neurology, London, UK; and Center for Imaging of Neurodegenerative Diseases (M.W.W.), VAMC San Francisco, CA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Wojta
authors.affiliation: From the Department of Neurology (J.C., K.W., G.C.), David Geffen School of Medicine, and Memory and Aging Center (J.S.Y., J.H.K., H.R., B.L.M., A.L.B.), Department of Neurology, University of California, Los Angeles; Department of Neurology (J.-T.Y., H.-F.W.), Qingdao Municipal Hospital, Nanjing Medical University, China; Clinical Neurochemistry Laboratory (H.Z., K.B.), Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg Mölndal, Sweden; Department of Molecular Neuroscience (H.Z.), UCL Institute of Neurology, London, UK; and Center for Imaging of Neurodegenerative Diseases (M.W.W.), VAMC San Francisco, CA.
authors.forename: Hui-Fu
authors.initials: HF
authors.lastname: Wang
authors.affiliation: From the Department of Neurology (J.C., K.W., G.C.), David Geffen School of Medicine, and Memory and Aging Center (J.S.Y., J.H.K., H.R., B.L.M., A.L.B.), Department of Neurology, University of California, Los Angeles; Department of Neurology (J.-T.Y., H.-F.W.), Qingdao Municipal Hospital, Nanjing Medical University, China; Clinical Neurochemistry Laboratory (H.Z., K.B.), Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg Mölndal, Sweden; Department of Molecular Neuroscience (H.Z.), UCL Institute of Neurology, London, UK; and Center for Imaging of Neurodegenerative Diseases (M.W.W.), VAMC San Francisco, CA.
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.affiliation: From the Department of Neurology (J.C., K.W., G.C.), David Geffen School of Medicine, and Memory and Aging Center (J.S.Y., J.H.K., H.R., B.L.M., A.L.B.), Department of Neurology, University of California, Los Angeles; Department of Neurology (J.-T.Y., H.-F.W.), Qingdao Municipal Hospital, Nanjing Medical University, China; Clinical Neurochemistry Laboratory (H.Z., K.B.), Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg Mölndal, Sweden; Department of Molecular Neuroscience (H.Z.), UCL Institute of Neurology, London, UK; and Center for Imaging of Neurodegenerative Diseases (M.W.W.), VAMC San Francisco, CA.
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.affiliation: From the Department of Neurology (J.C., K.W., G.C.), David Geffen School of Medicine, and Memory and Aging Center (J.S.Y., J.H.K., H.R., B.L.M., A.L.B.), Department of Neurology, University of California, Los Angeles; Department of Neurology (J.-T.Y., H.-F.W.), Qingdao Municipal Hospital, Nanjing Medical University, China; Clinical Neurochemistry Laboratory (H.Z., K.B.), Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg Mölndal, Sweden; Department of Molecular Neuroscience (H.Z.), UCL Institute of Neurology, London, UK; and Center for Imaging of Neurodegenerative Diseases (M.W.W.), VAMC San Francisco, CA.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Yokoyama
authors.affiliation: From the Department of Neurology (J.C., K.W., G.C.), David Geffen School of Medicine, and Memory and Aging Center (J.S.Y., J.H.K., H.R., B.L.M., A.L.B.), Department of Neurology, University of California, Los Angeles; Department of Neurology (J.-T.Y., H.-F.W.), Qingdao Municipal Hospital, Nanjing Medical University, China; Clinical Neurochemistry Laboratory (H.Z., K.B.), Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg Mölndal, Sweden; Department of Molecular Neuroscience (H.Z.), UCL Institute of Neurology, London, UK; and Center for Imaging of Neurodegenerative Diseases (M.W.W.), VAMC San Francisco, CA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Weiner
authors.affiliation: From the Department of Neurology (J.C., K.W., G.C.), David Geffen School of Medicine, and Memory and Aging Center (J.S.Y., J.H.K., H.R., B.L.M., A.L.B.), Department of Neurology, University of California, Los Angeles; Department of Neurology (J.-T.Y., H.-F.W.), Qingdao Municipal Hospital, Nanjing Medical University, China; Clinical Neurochemistry Laboratory (H.Z., K.B.), Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg Mölndal, Sweden; Department of Molecular Neuroscience (H.Z.), UCL Institute of Neurology, London, UK; and Center for Imaging of Neurodegenerative Diseases (M.W.W.), VAMC San Francisco, CA.
authors.forename: Joel H
authors.initials: JH
authors.lastname: Kramer
authors.affiliation: From the Department of Neurology (J.C., K.W., G.C.), David Geffen School of Medicine, and Memory and Aging Center (J.S.Y., J.H.K., H.R., B.L.M., A.L.B.), Department of Neurology, University of California, Los Angeles; Department of Neurology (J.-T.Y., H.-F.W.), Qingdao Municipal Hospital, Nanjing Medical University, China; Clinical Neurochemistry Laboratory (H.Z., K.B.), Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg Mölndal, Sweden; Department of Molecular Neuroscience (H.Z.), UCL Institute of Neurology, London, UK; and Center for Imaging of Neurodegenerative Diseases (M.W.W.), VAMC San Francisco, CA.
authors.forename: Howard
authors.initials: H
authors.lastname: Rosen
authors.affiliation: From the Department of Neurology (J.C., K.W., G.C.), David Geffen School of Medicine, and Memory and Aging Center (J.S.Y., J.H.K., H.R., B.L.M., A.L.B.), Department of Neurology, University of California, Los Angeles; Department of Neurology (J.-T.Y., H.-F.W.), Qingdao Municipal Hospital, Nanjing Medical University, China; Clinical Neurochemistry Laboratory (H.Z., K.B.), Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg Mölndal, Sweden; Department of Molecular Neuroscience (H.Z.), UCL Institute of Neurology, London, UK; and Center for Imaging of Neurodegenerative Diseases (M.W.W.), VAMC San Francisco, CA.
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Miller
authors.affiliation: From the Department of Neurology (J.C., K.W., G.C.), David Geffen School of Medicine, and Memory and Aging Center (J.S.Y., J.H.K., H.R., B.L.M., A.L.B.), Department of Neurology, University of California, Los Angeles; Department of Neurology (J.-T.Y., H.-F.W.), Qingdao Municipal Hospital, Nanjing Medical University, China; Clinical Neurochemistry Laboratory (H.Z., K.B.), Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg Mölndal, Sweden; Department of Molecular Neuroscience (H.Z.), UCL Institute of Neurology, London, UK; and Center for Imaging of Neurodegenerative Diseases (M.W.W.), VAMC San Francisco, CA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Coppola
authors.affiliation: From the Department of Neurology (J.C., K.W., G.C.), David Geffen School of Medicine, and Memory and Aging Center (J.S.Y., J.H.K., H.R., B.L.M., A.L.B.), Department of Neurology, University of California, Los Angeles; Department of Neurology (J.-T.Y., H.-F.W.), Qingdao Municipal Hospital, Nanjing Medical University, China; Clinical Neurochemistry Laboratory (H.Z., K.B.), Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg Mölndal, Sweden; Department of Molecular Neuroscience (H.Z.), UCL Institute of Neurology, London, UK; and Center for Imaging of Neurodegenerative Diseases (M.W.W.), VAMC San Francisco, CA. adam.boxer@ucsf.edu.
authors.forename: Adam L
authors.initials: AL
authors.lastname: Boxer
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000097:blood* / Q000134:cerebrospinal fluid / Q000235:genetics*; D053327:Apolipoprotein E4 / Q000235:genetics; D015415:Biomarkers / Q000097:blood / Q000134:cerebrospinal fluid; D060825:Cognitive Dysfunction / Q000097:blood* / Q000134:cerebrospinal fluid / Q000235:genetics*; D015331:Cohort Studies; D058068:Endophenotypes; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D014481:United States; D044465:White People / Q000235:genetics; D016875:tau Proteins / Q000097:blood* / Q000134:cerebrospinal fluid / Q000235:genetics*
chemical_list: D053327:Apolipoprotein E4; D015415:Biomarkers; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit; C054369:MAPT protein, human; D016875:tau Proteins; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein