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

Alzheimer’s Disease Neuroimaging Initiative (ADNI), The Alzheimer Disease Genetic Consortium (ADGC)

Research output: Contribution to journalArticle

31 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)839-856
Number of pages18
JournalActa Neuropathologica
Volume133
Issue number5
DOIs
StatePublished - May 1 2017

Fingerprint

Endophenotypes
Genome-Wide Association Study
Alzheimer Disease
Cerebrospinal Fluid
Genome
Genetic Loci
Computational Biology
Age of Onset
Amyloid
Disease Progression
Hippocampus
Biomarkers
Phenotype
Brain

Keywords

  • Alzheimer’s disease
  • Cerebrospinal fluid biomarkers
  • Endophenotype
  • Genome-wide association study

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Alzheimer’s Disease Neuroimaging Initiative (ADNI), & The Alzheimer Disease Genetic Consortium (ADGC) (2017). Genome-wide association study identifies four novel loci associated with Alzheimer’s endophenotypes and disease modifiers. Acta Neuropathologica, 133(5), 839-856. https://doi.org/10.1007/s00401-017-1685-y

Genome-wide association study identifies four novel loci associated with Alzheimer’s endophenotypes and disease modifiers. / Alzheimer’s Disease Neuroimaging Initiative (ADNI); The Alzheimer Disease Genetic Consortium (ADGC).

In: Acta Neuropathologica, Vol. 133, No. 5, 01.05.2017, p. 839-856.

Research output: Contribution to journalArticle

Alzheimer’s Disease Neuroimaging Initiative (ADNI) & The Alzheimer Disease Genetic Consortium (ADGC) 2017, 'Genome-wide association study identifies four novel loci associated with Alzheimer’s endophenotypes and disease modifiers', Acta Neuropathologica, vol. 133, no. 5, pp. 839-856. https://doi.org/10.1007/s00401-017-1685-y
Alzheimer’s Disease Neuroimaging Initiative (ADNI), The Alzheimer Disease Genetic Consortium (ADGC). Genome-wide association study identifies four novel loci associated with Alzheimer’s endophenotypes and disease modifiers. Acta Neuropathologica. 2017 May 1;133(5):839-856. https://doi.org/10.1007/s00401-017-1685-y
Alzheimer’s Disease Neuroimaging Initiative (ADNI) ; The Alzheimer Disease Genetic Consortium (ADGC). / Genome-wide association study identifies four novel loci associated with Alzheimer’s endophenotypes and disease modifiers. In: Acta Neuropathologica. 2017 ; Vol. 133, No. 5. pp. 839-856.
@article{219743ab02aa443784158a87d0daa4bc,
title = "Genome-wide association study identifies four novel loci associated with Alzheimer’s endophenotypes and disease modifiers",
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, Cerebrospinal fluid biomarkers, Endophenotype, Genome-wide association study",
author = "{Alzheimer’s Disease Neuroimaging Initiative (ADNI)} and {The Alzheimer Disease Genetic Consortium (ADGC)} and Yuetiva Deming and Zeran Li and Manav Kapoor and Oscar Harari and Del-Aguila, {Jorge L.} and Kathleen Black and David Carrell and Yefei Cai and Fernandez, {Maria Victoria} and John Budde and Shengmei Ma and Benjamin Saef and Bill Howells and Huang, {Kuan lin} and Sarah Bertelsen and Fagan, {Anne M.} and Holtzman, {David M.} and Morris, {John C.} and Sungeun Kim and Saykin, {Andrew J.} and {De Jager}, {Philip L.} and Marilyn Albert and Abhay Moghekar and Richard O’Brien and Matthias Riemenschneider and Petersen, {Ronald C.} and Kaj Blennow and Henrik Zetterberg and Lennart Minthon and {Van Deerlin}, {Vivianna M.} and Lee, {Virginia Man Yee} and Shaw, {Leslie M.} and Trojanowski, {John Q.} and Gerard Schellenberg and Haines, {Jonathan L.} and Richard Mayeux and Pericak-Vance, {Margaret A} and Farrer, {Lindsay A.} and Peskind, {Elaine R.} and Ge Li and {Di Narzo}, {Antonio F.} and Kauwe, {John S.K.} and Goate, {Alison M.} and Carlos Cruchaga",
year = "2017",
month = "5",
day = "1",
doi = "10.1007/s00401-017-1685-y",
language = "English (US)",
volume = "133",
pages = "839--856",
journal = "Acta Neuropathologica",
issn = "0001-6322",
publisher = "Springer Verlag",
number = "5",

}

TY - JOUR

T1 - Genome-wide association study identifies four novel loci associated with Alzheimer’s endophenotypes and disease modifiers

AU - Alzheimer’s Disease Neuroimaging Initiative (ADNI)

AU - The Alzheimer Disease Genetic Consortium (ADGC)

AU - Deming, Yuetiva

AU - Li, Zeran

AU - Kapoor, Manav

AU - Harari, Oscar

AU - Del-Aguila, Jorge L.

AU - Black, Kathleen

AU - Carrell, David

AU - Cai, Yefei

AU - Fernandez, Maria Victoria

AU - Budde, John

AU - Ma, Shengmei

AU - Saef, Benjamin

AU - Howells, Bill

AU - Huang, Kuan lin

AU - Bertelsen, Sarah

AU - Fagan, Anne M.

AU - Holtzman, David M.

AU - Morris, John C.

AU - Kim, Sungeun

AU - Saykin, Andrew J.

AU - De Jager, Philip L.

AU - Albert, Marilyn

AU - Moghekar, Abhay

AU - O’Brien, Richard

AU - Riemenschneider, Matthias

AU - Petersen, Ronald C.

AU - Blennow, Kaj

AU - Zetterberg, Henrik

AU - Minthon, Lennart

AU - Van Deerlin, Vivianna M.

AU - Lee, Virginia Man Yee

AU - Shaw, Leslie M.

AU - Trojanowski, John Q.

AU - Schellenberg, Gerard

AU - Haines, Jonathan L.

AU - Mayeux, Richard

AU - Pericak-Vance, Margaret A

AU - Farrer, Lindsay A.

AU - Peskind, Elaine R.

AU - Li, Ge

AU - Di Narzo, Antonio F.

AU - Kauwe, John S.K.

AU - Goate, Alison M.

AU - Cruchaga, Carlos

PY - 2017/5/1

Y1 - 2017/5/1

N2 - 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.

AB - 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.

KW - Alzheimer’s disease

KW - Cerebrospinal fluid biomarkers

KW - Endophenotype

KW - Genome-wide association study

UR - http://www.scopus.com/inward/record.url?scp=85014028462&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85014028462&partnerID=8YFLogxK

U2 - 10.1007/s00401-017-1685-y

DO - 10.1007/s00401-017-1685-y

M3 - Article

VL - 133

SP - 839

EP - 856

JO - Acta Neuropathologica

JF - Acta Neuropathologica

SN - 0001-6322

IS - 5

ER -