Acta Neuropathologica

, Volume 133, Issue 5, pp 839–856

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)
  • The Alzheimer Disease Genetic Consortium (ADGC)
  • John S. K. Kauwe
  • Alison M. Goate
  • Carlos Cruchaga
Original Paper

DOI: 10.1007/s00401-017-1685-y

Cite this article as:
Deming, Y., Li, Z., Kapoor, M. et al. Acta Neuropathol (2017) 133: 839. doi:10.1007/s00401-017-1685-y

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 Endophenotype Cerebrospinal fluid biomarkers Genome-wide association study 

Supplementary material

401_2017_1685_MOESM1_ESM.pdf (3.4 mb)
Supplementary material 1 (PDF 3468 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Yuetiva Deming
    • 1
  • Zeran Li
    • 1
  • Manav Kapoor
    • 2
  • Oscar Harari
    • 1
  • Jorge L. Del-Aguila
    • 1
  • Kathleen Black
    • 1
  • David Carrell
    • 1
  • Yefei Cai
    • 1
  • Maria Victoria Fernandez
    • 1
  • John Budde
    • 1
  • Shengmei Ma
    • 1
  • Benjamin Saef
    • 1
  • Bill Howells
    • 1
  • Kuan-lin Huang
    • 3
    • 4
  • Sarah Bertelsen
    • 2
  • 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. Saykin
    • 9
  • Philip L. De Jager
    • 11
    • 12
    • 13
  • Marilyn Albert
    • 14
  • Abhay Moghekar
    • 14
  • Richard O’Brien
    • 15
  • Matthias Riemenschneider
    • 16
  • Ronald C. Petersen
    • 17
  • Kaj Blennow
    • 18
    • 19
  • Henrik Zetterberg
    • 18
    • 19
    • 20
  • Lennart Minthon
    • 21
  • Vivianna M. Van Deerlin
    • 22
  • Virginia Man-Yee Lee
    • 22
  • Leslie M. Shaw
    • 22
  • John Q. Trojanowski
    • 22
  • Gerard Schellenberg
    • 22
  • Jonathan L. Haines
    • 23
  • Richard Mayeux
    • 24
  • Margaret A. Pericak-Vance
    • 25
  • Lindsay A. Farrer
    • 26
  • Elaine R. Peskind
    • 27
    • 28
  • Ge Li
    • 27
    • 29
  • Antonio F. Di Narzo
    • 30
  • Alzheimer’s Disease Neuroimaging Initiative (ADNI)
  • The Alzheimer Disease Genetic Consortium (ADGC)
  • John S. K. Kauwe
    • 31
  • Alison M. Goate
    • 2
  • Carlos Cruchaga
    • 1
    • 8
  1. 1.Department of PsychiatryWashington University School of MedicineSt. LouisUSA
  2. 2.Department of Neuroscience, Ronald M Loeb Center for Alzheimer’s DiseaseIcahn School of Medicine at Mount SinaiNew YorkUSA
  3. 3.Department of MedicineWashington University School of MedicineSt. LouisUSA
  4. 4.McDonnell Genome InstituteWashington University School of MedicineSt. LouisUSA
  5. 5.Department of NeurologyWashington University School of MedicineSt. LouisUSA
  6. 6.Knight Alzheimer’s Disease Research CenterWashington University School of MedicineSt. LouisUSA
  7. 7.Hope Center for Neurological DisordersWashington University School of MedicineSt. LouisUSA
  8. 8.Department of Developmental BiologyWashington University School of MedicineSt. LouisUSA
  9. 9.Indiana Alzheimer Disease Center and Center for NeuroimagingIndiana University School of MedicineIndianapolisUSA
  10. 10.Department of Electrical and Computer EngineeringState University of New YorkOswegoUSA
  11. 11.Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Institute for the NeurosciencesBrigham and Women’s HospitalBostonUSA
  12. 12.Harvard Medical SchoolBostonUSA
  13. 13.Program in Medical and Population GeneticsBroad Institute of Harvard University and M.I.T.CambridgeUSA
  14. 14.Department of NeurologyJohns Hopkins University School of MedicineBaltimoreUSA
  15. 15.Department of NeurologyDuke Medical CenterDurhamUSA
  16. 16.Clinic of Psychiatry and PsychotherapySaarland UniversityHomburg/SaarGermany
  17. 17.Department of NeurologyMayo ClinicRochesterUSA
  18. 18.Department of Psychiatry and Neurochemistry, Institute of Neuroscience and PhysiologyThe Sahlgrenska Academy at the University of GothenburgMölndalSweden
  19. 19.Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, Sahlgrenska University HospitalUniversity of GothenburgMölndalSweden
  20. 20.Department of Molecular NeuroscienceUCL Institute of NeurologyLondonUK
  21. 21.Clinical Memory Research Unit, Department of Clinical SciencesLund UniversityLundSweden
  22. 22.Department of Pathology and Laboratory MedicinePerelman School of Medicine at the University of PennsylvaniaPhiladelphiaUSA
  23. 23.Department of Molecular Physiology and Biophysics, Vanderbilt Center for Human Genetics ResearchVanderbilt UniversityNashvilleUSA
  24. 24.Department of Neurology, Taub Institute on Alzheimer’s Disease and the Aging Brain, and Gertrude H. Sergievsky CenterColumbia UniversityNew YorkUSA
  25. 25.The John P. Hussman Institute for Human Genomics, and Dr. John T. Macdonald Foundation Department of Human GeneticsUniversity of MiamiMiamiUSA
  26. 26.Departments of Biostatistics, Medicine (Genetics Program), Ophthalmology, Epidemiology, and NeurologyBoston UniversityBostonUSA
  27. 27.Department of Psychiatry and Behavioral SciencesUniversity of WashingtonSeattleUSA
  28. 28.VISN-20 Mental Illness Research, Education, and Clinical CenterVA Puget Sound Health Care SystemSeattleUSA
  29. 29.VISN-20 Geriatric Research, Education, and Clinical CenterVA Puget Sound Health Care SystemSeattleUSA
  30. 30.Department of Genetics and Genomic SciencesIcahn School of Medicine at Mount SinaiNew YorkUSA
  31. 31.Department of BiologyBrigham Young UniversityProvoUSA

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