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

Research output: Contribution to journalArticle


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.


  • Yuetiva Deming
  • Zeran Li
  • Manav Kapoor
  • Oscar Harari
  • Jorge L. Del-Aguila
  • Kathleen Black
  • David S. 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 D. 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
  • Alzheimer’S Disease Neuroimaging Initiative (Adni)
  • The Alzheimer Disease Genetics Consortium (ADGC)
External organisations
  • Washington University in St. Louis
  • Icahn School of Medicine at Mount Sinai
  • Indiana University
  • State University of New York at Oswego
  • Brigham and Women's Hospital / Harvard Medical School
  • Harvard Medical School
  • Broad Institute
  • Johns Hopkins University School of Medicine
  • Duke University
  • Saarland University
  • Mayo Clinic Minnesota
  • Sahlgrenska Academy
  • Sahlgrenska University Hospital
  • University College London
  • University of Pennsylvania
  • Vanderbilt University
  • Columbia University
  • University of Miami
  • Boston University
  • University of Washington
  • VA Puget Sound Health Care System
  • Brigham Young University
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Neurology
  • Neurosciences


  • Alzheimer’s disease, Cerebrospinal fluid biomarkers, Endophenotype, Genome-wide association study
Original languageEnglish
Pages (from-to)839-856
Number of pages18
JournalActa Neuropathologica
Issue number5
Publication statusPublished - 2017
Publication categoryResearch