title: A potential endophenotype for Alzheimer's disease: cerebrospinal fluid clusterin.
abstract: Genome-wide association studies have associated clusterin (CLU) variants with Alzheimer's disease (AD). However, the role of CLU on AD pathogenesis is not totally understood. We used cerebrospinal fluid (CSF) and plasma CLU levels as endophenotypes for genetic studies to understand the role of CLU in AD. CSF, but not plasma, CLU levels were significantly associated with AD status and CSF tau/amyloid-beta ratio, and highly correlated with CSF apolipoprotein E (APOE) levels. Several loci showed almost genome-wide significant associations including LINC00917 (p = 3.98 × 10(-7)) and interleukin 6 (IL6, p = 9.94 × 10(-6), in the entire data set and in the APOE ε4- individuals p = 7.40 × 10(-8)). Gene ontology analyses suggest that CSF CLU levels may be associated with wound healing and immune response which supports previous functional studies that demonstrated an association between CLU and IL6. CLU may play a role in AD by influencing immune system changes that have been observed in AD or by disrupting healing after neurodegeneration.
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Yuetiva
authors.initials: Y
authors.lastname: Deming
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Xia
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Yefei
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Jenny
authors.initials: J
authors.lastname: Lord
authors.affiliation: Institute of Psychological Medicine and Clinical Neurosciences, MRC Center for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Holmans
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Bertelsen
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA; Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: David
authors.initials: D
authors.lastname: Holtzman
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA; Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
authors.affiliation: Neuroscience Research Unit, Worldwide Research and Development, Pfizer, Inc., Groton, CT, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Bales
authors.affiliation: Neuroscience Research Unit, Worldwide Research and Development, Pfizer, Inc., Groton, CT, USA.
authors.forename: Eve H
authors.initials: EH
authors.lastname: Pickering
authors.affiliation: Department of Biology, Brigham Young University, Provo, UT, USA.
authors.forename: John
authors.initials: J
authors.lastname: Kauwe
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA; Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Alison
authors.initials: A
authors.lastname: Goate
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: ccruchaga@wustl.edu.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cruchaga
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000134:cerebrospinal fluid; D015415:Biomarkers / Q000134:cerebrospinal fluid; D051152:Clusterin / Q000097:blood / Q000134:cerebrospinal fluid* / Q000502:physiology; D058068:Endophenotypes; D005260:Female; D063990:Gene Ontology; D055106:Genome-Wide Association Study; D006801:Humans; D007109:Immunity / Q000235:genetics; D008297:Male; D009410:Nerve Degeneration / Q000235:genetics; D014945:Wound Healing / Q000235:genetics
chemical_list: D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D015415:Biomarkers; D051152:Clusterin
keywords: APOE; Alzheimer's disease; Cerebrospinal fluid; Clusterin; Gene ontology; Immune response