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

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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.

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Acknowledgements

We thank all the participants and their families, as well as the many institutions and their staff that provided support for all studies involved in this collaboration. We also thank the Alzheimer Disease Genetic Consortium (ADGC) for genotyping and providing data for the BIOCARD, UPENN, HB, SWEDEN, and MAYO cohorts. We thank the Cardiogenics (European Project reference LSHM-CT-2006-037593) project for providing data for the eQTL analysis. Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.

Author contributions

YD analyzed data and wrote the manuscript. ZL verified imputation with genotyped data. MK performed colocalization tests of GWAS and expression data. OH contributed conceptually to the analysis. KB performed genotyping for imputation verification. JLD-A performed disease progression analysis. DC, YC, MVF, JB, SM, BS, BH, KH, and SB prepared genetic data: performed imputation, cleaning, and calculated principal components. AMF, DMH, JCM, SK, AJS., PLDJ., MA, AM, RO, MR, RCP, KB, HZ, LM, VMVD, VM-YL, LMS, JQT, JLH, RM, MAP-V, LAF, ERP, GL, AFDN, ADNI, ADGC, JK and AG provided data. CC prepared the manuscript and supervised the project. All authors read and approved the manuscript.

Author information

Author notes

    Authors and Affiliations

    1. Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA

      Yuetiva Deming, Zeran Li, Oscar Harari, Jorge L. Del-Aguila, Kathleen Black, David Carrell, Yefei Cai, Maria Victoria Fernandez, John Budde, Shengmei Ma, Benjamin Saef, Bill Howells & Carlos Cruchaga

    2. Department of Neuroscience, Ronald M Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA

      Manav Kapoor, Sarah Bertelsen & Alison M. Goate

    3. Department of Medicine, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA

      Kuan-lin Huang

    4. McDonnell Genome Institute, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA

      Kuan-lin Huang

    5. Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO, 63110, USA

      Anne M. Fagan, David M. Holtzman & John C. Morris

    6. Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO, 63110, USA

      Anne M. Fagan, David M. Holtzman & John C. Morris

    7. Hope Center for Neurological Disorders, Washington University School of Medicine, 660 S. Euclid Ave. B8111, St. Louis, MO, 63110, USA

      Anne M. Fagan, David M. Holtzman & John C. Morris

    8. Department of Developmental Biology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO, 63110, USA

      David M. Holtzman, John C. Morris & Carlos Cruchaga

    9. Indiana Alzheimer Disease Center and Center for Neuroimaging, Indiana University School of Medicine, Indianapolis, IN, USA

      Sungeun Kim & Andrew J. Saykin

    10. Department of Electrical and Computer Engineering, State University of New York, Oswego, NY, 13126, USA

      Sungeun Kim

    11. Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Institute for the Neurosciences, Brigham and Women’s Hospital, Boston, MA, 02115, USA

      Philip L. De Jager

    12. Harvard Medical School, Boston, MA, 02115, USA

      Philip L. De Jager

    13. Program in Medical and Population Genetics, Broad Institute of Harvard University and M.I.T., Cambridge, MA, 02142, USA

      Philip L. De Jager

    14. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

      Marilyn Albert & Abhay Moghekar

    15. Department of Neurology, Duke Medical Center, Box 2900, Durham, NC, 27710, USA

      Richard O’Brien

    16. Clinic of Psychiatry and Psychotherapy, Saarland University, Homburg/Saar, Germany

      Matthias Riemenschneider

    17. Department of Neurology, Mayo Clinic, Rochester, MN, USA

      Ronald C. Petersen

    18. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden

      Kaj Blennow & Henrik Zetterberg

    19. Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, Sahlgrenska University Hospital, University of Gothenburg, Mölndal, Sweden

      Kaj Blennow & Henrik Zetterberg

    20. Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK

      Henrik Zetterberg

    21. Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Lund, Sweden

      Lennart Minthon

    22. Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

      Vivianna M. Van Deerlin, Virginia Man-Yee Lee, Leslie M. Shaw, John Q. Trojanowski & Gerard Schellenberg

    23. Department of Molecular Physiology and Biophysics, Vanderbilt Center for Human Genetics Research, Vanderbilt University, Nashville, TN, USA

      Jonathan L. Haines

    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

      Richard Mayeux

    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

      Margaret A. Pericak-Vance

    26. Departments of Biostatistics, Medicine (Genetics Program), Ophthalmology, Epidemiology, and Neurology, Boston University, Boston, MA, USA

      Lindsay A. Farrer

    27. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA

      Elaine R. Peskind & Ge Li

    28. VISN-20 Mental Illness Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA

      Elaine R. Peskind

    29. VISN-20 Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA

      Ge Li

    30. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

      Antonio F. Di Narzo

    31. Department of Biology, Brigham Young University, Provo, UT, USA

      John S. K. Kauwe

    Author notes

    1. J. S. K. Kauwe, A. M. Goate and C. Cruchaga equally contributed to this work.

      • Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf.

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        1. Yuetiva Deming
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        2. Zeran Li
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        Corresponding author

        Correspondence to Carlos Cruchaga.

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        Conflict of interest

        KB and HZ are co-founders of Brain Biomarker Solutions in Gothenburg AB, a GU Venture-based platform company at the University of Gothenburg, Sweden. A.M.G. serves on the SAB for Denali Therapeutics and is the inventor on a patent for MAPT mutations.

        Funding

        This work was supported by grants from the National Institutes of Health (R01AG044546, P01AG003991, RF1AG053303, R01AG035083, and R01NS085419), and the Alzheimer’s Association (NIRG-11-200110). This research was conducted while C.C. was a recipient of a New Investigator Award in Alzheimer’s disease from the American Federation for Aging Research. C.C. is a recipient of a BrightFocus Foundation Alzheimer’s Disease Research Grant (A2013359S). The recruitment and clinical characterization of research participants at Washington University were supported by NIH P50 AG05681, P01 AG03991, and P01 AG026276. ADGC is supported by grants from the NIH (#U01AG032984) and GERAD from the Wellcome Trust (GR082604MA) and the Medical Research Council (G0300429); additional support was provided by NCRAD (U24 AG21886), NACC (U01 AG016976), NIAGADS (U24-AG041689) and UPENN (P30 AG010124). Support for A.S. was provided by U01 AG024904, R01 AG19771, and P30 AG10133. P.D.J. received support from R01 AG048015. UW ADRC received funding from AG05136. S.K. received support from NIA R03AG050856, Alzheimer’s Association, Michael J. Fox Foundation, and ARUK Biomarkers Across Neurodegenerative Diseases (BAND). M.R. received support from the German Federal Ministry of Education and Research (BMBF) National Genome Research Network (NGFN) Grant No. 01GS08125 and through the Helmholtz Alliance for Mental Health in an Aging Society (HELMA) Grant No. Ha-15. This work was supported by access to equipment made possible by the Hope Center for Neurological Disorders and the Departments of Neurology and Psychiatry at Washington University School of Medicine.

        Additional information

        Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf.

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        Deming, Y., Li, Z., Kapoor, M. et al. Genome-wide association study identifies four novel loci associated with Alzheimer’s endophenotypes and disease modifiers. Acta Neuropathol 133, 839–856 (2017). https://doi.org/10.1007/s00401-017-1685-y

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