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28.02.2017 | Original Paper

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

verfasst von: 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, John S. K. Kauwe, Alison M. Goate, Carlos Cruchaga, Alzheimer’s Disease Neuroimaging Initiative (ADNI), The Alzheimer Disease Genetic Consortium (ADGC)

Erschienen in: Acta Neuropathologica | Ausgabe 5/2017

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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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Titel: Genome-wide association study identifies four novel loci associated with Alzheimer’s endophenotypes and disease modifiers
verfasst von: 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
John S. K. Kauwe
Alison M. Goate
Carlos Cruchaga
Alzheimer’s Disease Neuroimaging Initiative (ADNI)
The Alzheimer Disease Genetic Consortium (ADGC)
Publikationsdatum: 28.02.2017
Verlag: Springer Berlin Heidelberg
Erschienen in: Acta Neuropathologica / Ausgabe 5/2017
Print ISSN: 0001-6322
Elektronische ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-017-1685-y

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