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  • Deming, YuetivaWashington University in St. Louis (author)

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

  • Article/chapterEnglish2017

Publisher, publication year, extent ...

  • 2017-02-28
  • Springer Science and Business Media LLC,2017
  • 18 s.

Numbers

  • LIBRIS-ID:oai:lup.lub.lu.se:e0da950d-3e1b-428a-9f8b-09267d4f478e
  • https://lup.lub.lu.se/record/e0da950d-3e1b-428a-9f8b-09267d4f478eURI
  • https://doi.org/10.1007/s00401-017-1685-yDOI
  • https://gup.ub.gu.se/publication/251980URI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:art swepub-publicationtype
  • Subject category:ref swepub-contenttype

Notes

  • 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.

Subject headings and genre

Added entries (persons, corporate bodies, meetings, titles ...)

  • Li, ZeranWashington University in St. Louis (author)
  • Kapoor, ManavIcahn School of Medicine at Mount Sinai (author)
  • Harari, OscarWashington University in St. Louis (author)
  • Del-Aguila, Jorge L.Washington University in St. Louis (author)
  • Black, KathleenWashington University in St. Louis (author)
  • Carrell, David S.Washington University in St. Louis (author)
  • Cai, YefeiWashington University in St. Louis (author)
  • Fernandez, Maria VictoriaWashington University in St. Louis (author)
  • Budde, JohnWashington University in St. Louis (author)
  • Ma, ShengmeiWashington University in St. Louis (author)
  • Saef, BenjaminWashington University in St. Louis (author)
  • Howells, BillWashington University in St. Louis (author)
  • Huang, Kuan linWashington University in St. Louis (author)
  • Bertelsen, SarahIcahn School of Medicine at Mount Sinai (author)
  • Fagan, Anne MWashington University in St. Louis (author)
  • Holtzman, David M.Washington University in St. Louis (author)
  • Morris, John CWashington University in St. Louis (author)
  • Kim, SungeunIndiana University,State University of New York at Oswego (author)
  • Saykin, Andrew J.Indiana University (author)
  • De Jager, Philip LBroad Institute,Harvard Medical School,Brigham and Women's Hospital / Harvard Medical School (author)
  • Albert, MarilynJohns Hopkins University School of Medicine (author)
  • Moghekar, AbhayJohns Hopkins University School of Medicine (author)
  • O’Brien, RichardDuke University (author)
  • Riemenschneider, MatthiasSaarland University (author)
  • Petersen, Ronald CMayo Clinic Minnesota (author)
  • Blennow, KajGothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry(Swepub:gu)xbleka (author)
  • Zetterberg, HenrikGothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry(Swepub:gu)xzethe (author)
  • Minthon, LennartLund University,Lunds universitet,Klinisk minnesforskning,Forskargrupper vid Lunds universitet,Clinical Memory Research,Lund University Research Groups(Swepub:lu)psyk-lmi (author)
  • Van Deerlin, Vivianna MUniversity of Pennsylvania (author)
  • Lee, Virginia Man YeeUniversity of Pennsylvania (author)
  • Shaw, Leslie M.University of Pennsylvania (author)
  • Trojanowski, John QUniversity of Pennsylvania (author)
  • Schellenberg, Gerard D.University of Pennsylvania (author)
  • Haines, Jonathan L.Vanderbilt University (author)
  • Mayeux, RichardColumbia University (author)
  • Pericak-Vance, Margaret A.University of Miami (author)
  • Farrer, Lindsay A.Boston University (author)
  • Peskind, Elaine R.University of Washington,VA Puget Sound Health Care System (author)
  • Li, GeUniversity of Washington,VA Puget Sound Health Care System (author)
  • Di Narzo, Antonio F.Icahn School of Medicine at Mount Sinai (author)
  • Kauwe, John S KBrigham Young University (author)
  • Goate, Alison M.Icahn School of Medicine at Mount Sinai (author)
  • Cruchaga, CarlosWashington University in St. Louis (author)
  • Washington University in St. LouisIcahn School of Medicine at Mount Sinai (creator_code:org_t)
  • Alzheimer's Disease Neuroimaging Initiative
  • The Alzheimer Disease Genetics Consortium (ADGC)

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  • In:Acta Neuropathologica: Springer Science and Business Media LLC133:5, s. 839-8560001-63221432-0533

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