Genome-wide association study identifies four novel loci associated with Alzheimer's endophenotypes and disease modifiers

Yuetiva Deming; Zeran Li; Manav Kapoor; Oscar Harari; Jorge L Del-Aguila; Kathleen Black; David Carrell; Yefei Cai; Maria Victoria Fernandez; John Budde; Shengmei Ma; Benjamin Saef; Bill Howells; Kuan-Lin Huang; Sarah Bertelsen; Anne M Fagan; David M Holtzman; John C Morris; Sungeun Kim; Andrew J Saykin; Philip L De Jager; Marilyn Albert; Abhay Moghekar; Richard O'Brien; Matthias Riemenschneider; Ronald C Petersen; Kaj Blennow; Henrik Zetterberg; Lennart Minthon; Vivianna M Van Deerlin; Virginia Man-Yee Lee; Leslie M Shaw; John Q Trojanowski; Gerard Schellenberg; Jonathan L Haines; Richard Mayeux; Margaret A Pericak-Vance; Lindsay A Farrer; Elaine R Peskind; Ge Li; Antonio F Di Narzo; John S K Kauwe; Alison M Goate; Carlos Cruchaga

doi:10.1007/s00401-017-1685-y

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Genome-wide association study identifies four novel loci associated with Alzheimer's endophenotypes and disease modifiers

Journal article

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Genome-wide association study identifies four novel loci associated with Alzheimer's endophenotypes and disease modifiers

Yuetiva Deming, Zeran Li, Manav Kapoor, Oscar Harari, Jorge L Del-Aguila, Kathleen Black, David Carrell, Yefei Cai, Maria Victoria Fernandez, John Budde, …

Acta neuropathologica, Vol.133(5), pp.839-856

2017-05

DOI: https://doi.org/10.1007/s00401-017-1685-y

PMCID: PMC5613285

PMID: 28247064

Abstract

Genetic Predisposition to Disease

Genome-Wide Association Study

Endophenotypes - cerebrospinal fluid

Humans

Middle Aged

Risk Factors

Biomarkers - analysis

Genotype

tau Proteins - cerebrospinal fluid

Genetic Loci

Alzheimer Disease - cerebrospinal fluid

Disease Progression

tau Proteins - genetics

Amyloid beta-Peptides - genetics

Apolipoproteins E - genetics

Aged, 80 and over

Adult

Aged

Alzheimer Disease - genetics

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 (Aβ ), tau, and phosphorylated tau (ptau ) 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 ptau , including loci that have also been associated with AD risk or brain-related phenotypes. Two novel loci associated with Aβ near GLIS1 on 1p32.3 (β = -0.059, P = 2.08 × 10 ) and within SERPINB1 on 6p25 (β = -0.025, P = 1.72 × 10 ) were also associated with AD risk (GLIS1: OR = 1.105, P = 3.43 × 10 ), disease progression (GLIS1: β = 0.277, P = 1.92 × 10 ), and age at onset (SERPINB1: β = 0.043, P = 4.62 × 10 ). 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 Aβ (P = 0.001 and P = 0.009, respectively) and the INPP5D locus may affect ptau levels (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.

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.52 Neurodegenerative Diseases; 1.52.57 Alzheimer's Disease
Web Of Science research areas: Clinical Neurology; Neurosciences; Pathology
ESI research areas: Neuroscience & Behavior

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Title: Genome-wide association study identifies four novel loci associated with Alzheimer's endophenotypes and disease modifiers
Creators: Yuetiva Deming - Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA
Zeran Li - Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA
Manav Kapoor - Department of Neuroscience, Ronald M Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Oscar Harari - Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA
Jorge L Del-Aguila - Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA
Kathleen Black - Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA
David Carrell - Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA
Yefei Cai - Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA
Maria Victoria Fernandez - Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA
John Budde - Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA
Shengmei Ma - Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA
Benjamin Saef - Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA
Bill Howells - Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA
Kuan-Lin Huang - McDonnell Genome Institute, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA
Sarah Bertelsen - Department of Neuroscience, Ronald M Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Anne M Fagan - Hope Center for Neurological Disorders, Washington University School of Medicine, 660 S. Euclid Ave. B8111, St. Louis, MO, 63110, USA
David M Holtzman - Department of Developmental Biology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO, 63110, USA
John C Morris - Department of Developmental Biology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO, 63110, USA
Sungeun Kim - Department of Electrical and Computer Engineering, State University of New York, Oswego, NY, 13126, USA
Andrew J Saykin - Indiana Alzheimer Disease Center and Center for Neuroimaging, Indiana University School of Medicine, Indianapolis, IN, USA
Philip L De Jager - Program in Medical and Population Genetics, Broad Institute of Harvard University and M.I.T., Cambridge, MA, 02142, USA
Marilyn Albert - Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Abhay Moghekar - Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Richard O'Brien - Department of Neurology, Duke Medical Center, Box 2900, Durham, NC, 27710, USA
Matthias Riemenschneider - Clinic of Psychiatry and Psychotherapy, Saarland University, Homburg/Saar, Germany
Ronald C Petersen - Department of Neurology, Mayo Clinic, Rochester, MN, USA
Kaj Blennow - Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, Sahlgrenska University Hospital, University of Gothenburg, Mölndal, Sweden
Henrik Zetterberg - Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK
Lennart Minthon - Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Lund, Sweden
Vivianna M Van Deerlin - Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
Virginia Man-Yee Lee - Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
Leslie M Shaw - Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
John Q Trojanowski - Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
Gerard Schellenberg - Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
Jonathan L Haines - Department of Molecular Physiology and Biophysics, Vanderbilt Center for Human Genetics Research, Vanderbilt University, Nashville, TN, USA
Richard Mayeux - Department of Neurology, Taub Institute on Alzheimer's Disease and the Aging Brain, and Gertrude H. Sergievsky Center, Columbia University, New York, NY, USA
Margaret A Pericak-Vance - The John P. Hussman Institute for Human Genomics, and Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, FL, USA
Lindsay A Farrer - Departments of Biostatistics, Medicine (Genetics Program), Ophthalmology, Epidemiology, and Neurology, Boston University, Boston, MA, USA
Elaine R Peskind - VISN-20 Mental Illness Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA
Ge Li - VISN-20 Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA
Antonio F Di Narzo - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
John S K Kauwe - Department of Biology, Brigham Young University, Provo, UT, USA
Alison M Goate - Department of Neuroscience, Ronald M Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Carlos Cruchaga - Department of Developmental Biology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO, 63110, USA. ccruchaga@wustl.edu
Publication Details: Acta neuropathologica, Vol.133(5), pp.839-856
Publisher: Germany
Grant note: P01 AG003991 / NIA NIH HHS P30 AG010124 / NIA NIH HHS R01 LM012535 / NLM NIH HHS U24 AG021886 / NIA NIH HHS RF1 AG053303 / NIA NIH HHS P30 AG013846 / NIA NIH HHS S10 OD018522 / NIH HHS P50 AG005136 / NIA NIH HHS P01 AG026276 / NIA NIH HHS R01 AG054060 / NIA NIH HHS U01 AG032984 / NIA NIH HHS P50 AG005681 / NIA NIH HHS R01 AG044546 / NIA NIH HHS R25 DA027995 / NIDA NIH HHS
Academic Unit: Miller School of Medicine; John P. Hussman Institute for Human Genomics; UMMG Dept of Human Genetics (Dr. John T. Macdonald Foundation)
Language: English
Resource Type: Journal article
PMID: 28247064
PMCID: PMC5613285
Record Identifier: 991031577818602976