title: Genome-wide association study identifies four novel loci associated with Alzheimer's endophenotypes and disease modifiers.
abstract: More than 20 genetic loci have been associated with risk for Alzheimer's disease (AD), but reported genome-wide significant loci do not account for all the estimated heritability and provide little information about underlying biological mechanisms. Genetic studies using intermediate quantitative traits such as biomarkers, or endophenotypes, benefit from increased statistical power to identify variants that may not pass the stringent multiple test correction in case-control studies. Endophenotypes also contain additional information helpful for identifying variants and genes associated with other aspects of disease, such as rate of progression or onset, and provide context to interpret the results from genome-wide association studies (GWAS). We conducted GWAS of amyloid beta (Aβ42), tau, and phosphorylated tau (ptau181) levels in cerebrospinal fluid (CSF) from 3146 participants across nine studies to identify novel variants associated with AD. Five genome-wide significant loci (two novel) were associated with ptau181, including loci that have also been associated with AD risk or brain-related phenotypes. Two novel loci associated with Aβ42near GLIS1 on 1p32.3 (β = -0.059, P = 2.08 × 10-8) and within SERPINB1 on 6p25 (β = -0.025, P = 1.72 × 10-8) were also associated with AD risk (GLIS1: OR = 1.105, P = 3.43 × 10-2), disease progression (GLIS1: β = 0.277, P = 1.92 × 10-2), and age at onset (SERPINB1: β = 0.043, P = 4.62 × 10-3). Bioinformatics indicate that the intronic SERPINB1 variant (rs316341) affects expression of SERPINB1 in various tissues, including the hippocampus, suggesting that SERPINB1 influences AD through an Aβ-associated mechanism. Analyses of known AD risk loci suggest CLU and FERMT2 may influence CSF Aβ42(P = 0.001 and P = 0.009, respectively) and the INPP5D locus may affect ptau181levels (P = 0.009); larger studies are necessary to verify these results. Together the findings from this study can be used to inform future AD studies.
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA.
authors.forename: Yuetiva
authors.initials: Y
authors.lastname: Deming
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA.
authors.forename: Zeran
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Neuroscience, Ronald M Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Manav
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authors.lastname: Kapoor
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA.
authors.forename: Oscar
authors.initials: O
authors.lastname: Harari
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA.
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Del-Aguila
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Black
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA.
authors.forename: David
authors.initials: D
authors.lastname: Carrell
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA.
authors.forename: Yefei
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA.
authors.forename: Maria Victoria
authors.initials: MV
authors.lastname: Fernandez
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA.
authors.forename: John
authors.initials: J
authors.lastname: Budde
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA.
authors.forename: Shengmei
authors.initials: S
authors.lastname: Ma
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Saef
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA.
authors.forename: Bill
authors.initials: B
authors.lastname: Howells
authors.affiliation: Department of Medicine, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA.|McDonnell Genome Institute, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA.
authors.forename: Kuan-Lin
authors.initials: KL
authors.lastname: Huang
authors.affiliation: Department of Neuroscience, Ronald M Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Bertelsen
authors.affiliation: Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO, 63110, USA.|Knight Alzheimer's Disease Research Center, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO, 63110, USA.|Hope Center for Neurological Disorders, Washington University School of Medicine, 660 S. Euclid Ave. B8111, St. Louis, MO, 63110, USA.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Fagan
authors.affiliation: Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO, 63110, USA.|Knight Alzheimer's Disease Research Center, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO, 63110, USA.|Hope Center for Neurological Disorders, Washington University School of Medicine, 660 S. Euclid Ave. B8111, St. Louis, MO, 63110, USA.|Department of Developmental Biology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO, 63110, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
authors.affiliation: Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO, 63110, USA.|Knight Alzheimer's Disease Research Center, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO, 63110, USA.|Hope Center for Neurological Disorders, Washington University School of Medicine, 660 S. Euclid Ave. B8111, St. Louis, MO, 63110, USA.|Department of Developmental Biology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO, 63110, USA.
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authors.initials: JC
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authors.affiliation: Indiana Alzheimer Disease Center and Center for Neuroimaging, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Electrical and Computer Engineering, State University of New York, Oswego, NY, 13126, USA.
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authors.affiliation: Indiana Alzheimer Disease Center and Center for Neuroimaging, Indiana University School of Medicine, Indianapolis, IN, USA.
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authors.initials: AJ
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authors.affiliation: Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Institute for the Neurosciences, Brigham and Women's Hospital, Boston, MA, 02115, USA.|Harvard Medical School, Boston, MA, 02115, USA.|Program in Medical and Population Genetics, Broad Institute of Harvard University and M.I.T., Cambridge, MA, 02142, USA.
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authors.initials: PL
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authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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authors.affiliation: Department of Neurology, Duke Medical Center, Box 2900, Durham, NC, 27710, USA.
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authors.affiliation: Clinic of Psychiatry and Psychotherapy, Saarland University, Homburg/Saar, Germany.
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authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
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authors.initials: RC
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authors.affiliation: Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.|Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, Sahlgrenska University Hospital, University of Gothenburg, Mölndal, Sweden.
authors.forename: Kaj
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authors.affiliation: Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.|Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, Sahlgrenska University Hospital, University of Gothenburg, Mölndal, Sweden.|Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK.
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authors.initials: H
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authors.affiliation: Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Lennart
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authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
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authors.initials: VM
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authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
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authors.initials: VM
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authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
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authors.initials: LM
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authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
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authors.initials: JQ
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authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
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authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt Center for Human Genetics Research, Vanderbilt University, Nashville, TN, USA.
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authors.initials: LA
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authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.|VISN-20 Mental Illness Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA.
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authors.initials: ER
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authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.|VISN-20 Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA.
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authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA. ccruchaga@wustl.edu.|Department of Developmental Biology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO, 63110, USA. ccruchaga@wustl.edu.
authors.forename: Carlos
authors.identifier: 0000-0002-0276-2899
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mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics; D015415:Biomarkers / Q000032:analysis; D018450:Disease Progression; D058068:Endophenotypes / Q000134:cerebrospinal fluid; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D012307:Risk Factors; D016875:tau Proteins / Q000134:cerebrospinal fluid / Q000235:genetics*
chemical_list: D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D015415:Biomarkers; D016875:tau Proteins
keywords: Alzheimer’s disease; Cerebrospinal fluid biomarkers; Endophenotype; Genome-wide association study