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; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Alzheimer Disease Genetic Consortium (ADGC); John S K Kauwe; Alison M Goate; Carlos Cruchaga

doi:10.1007/s00401-017-1685-y

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

Acta Neuropathol. 2017 May;133(5):839-856. doi: 10.1007/s00401-017-1685-y. Epub 2017 Feb 28.

Authors

Yuetiva Deming¹, Zeran Li¹, Manav Kapoor², Oscar Harari¹, Jorge L Del-Aguila¹, Kathleen Black¹, David Carrell¹, Yefei Cai¹, Maria Victoria Fernandez¹, John Budde¹, Shengmei Ma¹, Benjamin Saef¹, Bill Howells¹, Kuan-Lin Huang^{3

4}, Sarah Bertelsen², Anne M Fagan^{5

6

7}, David M Holtzman^{5

6

7

8}, John C Morris^{5

6

7

8}, Sungeun Kim^{9

10}, Andrew J Saykin⁹, Philip L De Jager^{11

12

13}, Marilyn Albert¹⁴, Abhay Moghekar¹⁴, Richard O'Brien¹⁵, Matthias Riemenschneider¹⁶, Ronald C Petersen¹⁷, Kaj Blennow^{18

19}, Henrik Zetterberg^{18

19

20}, Lennart Minthon²¹, Vivianna M Van Deerlin²², Virginia Man-Yee Lee²², Leslie M Shaw²², John Q Trojanowski²², Gerard Schellenberg²², Jonathan L Haines²³, Richard Mayeux²⁴, Margaret A Pericak-Vance²⁵, Lindsay A Farrer²⁶, Elaine R Peskind^{27

28}, Ge Li^{27

29}, Antonio F Di Narzo³⁰; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Alzheimer Disease Genetic Consortium (ADGC); John S K Kauwe³¹, Alison M Goate², Carlos Cruchaga^{32

33}

Affiliations

¹ Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA.
² Department of Neuroscience, Ronald M Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³ Department of Medicine, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA.
⁴ McDonnell Genome Institute, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA.
⁵ Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO, 63110, USA.
⁶ Knight Alzheimer's Disease Research Center, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO, 63110, USA.
⁷ Hope Center for Neurological Disorders, Washington University School of Medicine, 660 S. Euclid Ave. B8111, St. Louis, MO, 63110, USA.
⁸ Department of Developmental Biology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO, 63110, USA.
⁹ Indiana Alzheimer Disease Center and Center for Neuroimaging, Indiana University School of Medicine, Indianapolis, IN, USA.
¹⁰ Department of Electrical and Computer Engineering, State University of New York, Oswego, NY, 13126, USA.
¹¹ Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Institute for the Neurosciences, Brigham and Women's Hospital, Boston, MA, 02115, USA.
¹² Harvard Medical School, Boston, MA, 02115, USA.
¹³ Program in Medical and Population Genetics, Broad Institute of Harvard University and M.I.T., Cambridge, MA, 02142, USA.
¹⁴ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁵ Department of Neurology, Duke Medical Center, Box 2900, Durham, NC, 27710, USA.
¹⁶ Clinic of Psychiatry and Psychotherapy, Saarland University, Homburg/Saar, Germany.
¹⁷ Department of Neurology, Mayo Clinic, Rochester, MN, USA.
¹⁸ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
¹⁹ Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, Sahlgrenska University Hospital, University of Gothenburg, Mölndal, Sweden.
²⁰ Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK.
²¹ Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Lund, Sweden.
²² Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
²³ Department of Molecular Physiology and Biophysics, Vanderbilt Center for Human Genetics Research, Vanderbilt University, Nashville, TN, USA.
²⁴ Department of Neurology, Taub Institute on Alzheimer's Disease and the Aging Brain, and Gertrude H. Sergievsky Center, Columbia University, New York, NY, USA.
²⁵ The John P. Hussman Institute for Human Genomics, and Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, FL, USA.
²⁶ Departments of Biostatistics, Medicine (Genetics Program), Ophthalmology, Epidemiology, and Neurology, Boston University, Boston, MA, USA.
²⁷ Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.
²⁸ VISN-20 Mental Illness Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA.
²⁹ VISN-20 Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA.
³⁰ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³¹ Department of Biology, Brigham Young University, Provo, UT, USA.
³² Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA. ccruchaga@wustl.edu.
³³ Department of Developmental Biology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO, 63110, USA. ccruchaga@wustl.edu.

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 Aβ₄₂ near 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 ptau₁₈₁ 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.

Keywords: Alzheimer’s disease; Cerebrospinal fluid biomarkers; Endophenotype; Genome-wide association study.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Adult
Aged
Aged, 80 and over
Alzheimer Disease / cerebrospinal fluid
Alzheimer Disease / genetics*
Amyloid beta-Peptides / genetics*
Apolipoproteins E / genetics
Biomarkers / analysis
Disease Progression
Endophenotypes / cerebrospinal fluid
Genetic Loci
Genetic Predisposition to Disease*
Genome-Wide Association Study*
Genotype
Humans
Middle Aged
Risk Factors
tau Proteins / cerebrospinal fluid
tau Proteins / genetics*

Substances

Amyloid beta-Peptides
Apolipoproteins E
Biomarkers
tau Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding