Advanced

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

Deming, Yuetiva; Li, Zeran; Kapoor, Manav; Harari, Oscar; Del-Aguila, Jorge L.; Black, Kathleen; Carrell, David S.; Cai, Yefei; Fernandez, Maria Victoria and Budde, John, et al. (2017) In Acta Neuropathologica 133(5). p.839-856
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... (More)

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.

(Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Alzheimer’s disease, Cerebrospinal fluid biomarkers, Endophenotype, Genome-wide association study
in
Acta Neuropathologica
volume
133
issue
5
pages
18 pages
publisher
Springer
external identifiers
  • scopus:85014028462
  • wos:000399397300010
ISSN
0001-6322
DOI
10.1007/s00401-017-1685-y
language
English
LU publication?
yes
id
e0da950d-3e1b-428a-9f8b-09267d4f478e
date added to LUP
2017-03-17 16:21:34
date last changed
2018-08-12 04:34:48
@article{e0da950d-3e1b-428a-9f8b-09267d4f478e,
  abstract     = {<p>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 (Aβ<sub>42</sub>), tau, and phosphorylated tau (ptau<sub>181</sub>) 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 ptau<sub>181</sub>, including loci that have also been associated with AD risk or brain-related phenotypes. Two novel loci associated with Aβ<sub>42</sub> near GLIS1 on 1p32.3 (β = −0.059, P = 2.08 × 10<sup>−8</sup>) and within SERPINB1 on 6p25 (β = −0.025, P = 1.72 × 10<sup>−8</sup>) were also associated with AD risk (GLIS1: OR = 1.105, P = 3.43 × 10<sup>−2</sup>), disease progression (GLIS1: β = 0.277, P = 1.92 × 10<sup>−2</sup>), and age at onset (SERPINB1: β = 0.043, P = 4.62 × 10<sup>−3</sup>). 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 Aβ<sub>42</sub> (P = 0.001 and P = 0.009, respectively) and the INPP5D locus may affect ptau<sub>181</sub> 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.</p>},
  author       = {Deming, Yuetiva and Li, Zeran and Kapoor, Manav and Harari, Oscar and Del-Aguila, Jorge L. and Black, Kathleen and Carrell, David S. and Cai, Yefei and Fernandez, Maria Victoria and Budde, John and Ma, Shengmei and Saef, Benjamin and Howells, Bill and Huang, Kuan lin and Bertelsen, Sarah and Fagan, Anne M and Holtzman, David M. and Morris, John C and Kim, Sungeun and Saykin, Andrew J. and De Jager, Philip L and Albert, Marilyn and Moghekar, Abhay and O’Brien, Richard and Riemenschneider, Matthias and Petersen, Ronald C and Blennow, Kaj and Zetterberg, Henrik and Minthon, Lennart and Van Deerlin, Vivianna M and Lee, Virginia Man Yee and Shaw, Leslie M. and Trojanowski, John Q and Schellenberg, Gerard D. and Haines, Jonathan L. and Mayeux, Richard and Pericak-Vance, Margaret A. and Farrer, Lindsay A. and Peskind, Elaine R. and Li, Ge and Di Narzo, Antonio F. and Kauwe, John S K and Goate, Alison M. and Cruchaga, Carlos and ,  and , },
  issn         = {0001-6322},
  keyword      = {Alzheimer’s disease,Cerebrospinal fluid biomarkers,Endophenotype,Genome-wide association study},
  language     = {eng},
  month        = {02},
  number       = {5},
  pages        = {839--856},
  publisher    = {Springer},
  series       = {Acta Neuropathologica},
  title        = {Genome-wide association study identifies four novel loci associated with Alzheimer’s endophenotypes and disease modifiers},
  url          = {http://dx.doi.org/10.1007/s00401-017-1685-y},
  volume       = {133},
  year         = {2017},
}