Non-coding variability at the APOE locus contributes to the Alzheimer’s risk

Alzheimer’s Disease Neuroimaging Initiative

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Alzheimer’s disease (AD) is a leading cause of mortality in the elderly. While the coding change of APOE-ε4 is a key risk factor for late-onset AD and has been believed to be the only risk factor in the APOE locus, it does not fully explain the risk effect conferred by the locus. Here, we report the identification of AD causal variants in PVRL2 and APOC1 regions in proximity to APOE and define common risk haplotypes independent of APOE-ε4 coding change. These risk haplotypes are associated with changes of AD-related endophenotypes including cognitive performance, and altered expression of APOE and its nearby genes in the human brain and blood. High-throughput genome-wide chromosome conformation capture analysis further supports the roles of these risk haplotypes in modulating chromatin states and gene expression in the brain. Our findings provide compelling evidence for additional risk factors in the APOE locus that contribute to AD pathogenesis.

Original languageEnglish (US)
Article number3310
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

Fingerprint

loci
Alzheimer Disease
Haplotypes
Endophenotypes
brain
Brain
coding
Genes
Chromatin
pathogenesis
chromatin
genome
mortality
gene expression
chromosomes
Chromosomes
Genome
Gene expression
genes
Gene Expression

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Non-coding variability at the APOE locus contributes to the Alzheimer’s risk. / Alzheimer’s Disease Neuroimaging Initiative.

In: Nature communications, Vol. 10, No. 1, 3310, 01.12.2019.

Research output: Contribution to journalArticle

Alzheimer’s Disease Neuroimaging Initiative. / Non-coding variability at the APOE locus contributes to the Alzheimer’s risk. In: Nature communications. 2019 ; Vol. 10, No. 1.
@article{e5f1ea45b1394241aa8aa65044d218a3,
title = "Non-coding variability at the APOE locus contributes to the Alzheimer’s risk",
abstract = "Alzheimer’s disease (AD) is a leading cause of mortality in the elderly. While the coding change of APOE-ε4 is a key risk factor for late-onset AD and has been believed to be the only risk factor in the APOE locus, it does not fully explain the risk effect conferred by the locus. Here, we report the identification of AD causal variants in PVRL2 and APOC1 regions in proximity to APOE and define common risk haplotypes independent of APOE-ε4 coding change. These risk haplotypes are associated with changes of AD-related endophenotypes including cognitive performance, and altered expression of APOE and its nearby genes in the human brain and blood. High-throughput genome-wide chromosome conformation capture analysis further supports the roles of these risk haplotypes in modulating chromatin states and gene expression in the brain. Our findings provide compelling evidence for additional risk factors in the APOE locus that contribute to AD pathogenesis.",
author = "{Alzheimer’s Disease Neuroimaging Initiative} and Xiaopu Zhou and Yu Chen and Mok, {Kin Y.} and Kwok, {Timothy C.Y.} and Mok, {Vincent C.T.} and Qihao Guo and Ip, {Fanny C.} and Yuewen Chen and Nandita Mullapudi and Weiner, {Michael W.} and Paul Aisen and Ronald Petersen and Jack, {Clifford R.} and William Jagust and Trojanowski, {John Q.} and Toga, {Arthur W.} and Laurel Beckett and Green, {Robert C.} and Saykin, {Andrew J.} and John Morris and Shaw, {Leslie M.} and Zaven Khachaturian and Greg Sorensen and Lew Kuller and Marcus Raichle and Steven Paul and Peter Davies and Howard Fillit and Franz Hefti and David Holtzman and Mesulam, {Marek M.} and William Potter and Peter Snyder and Adam Schwartz and Tom Montine and Thomas, {Ronald G.} and Michael Donohue and Sarah Walter and Devon Gessert and Tamie Sather and Gus Jiminez and Danielle Harvey and Matthew Bernstein and Paul Thompson and Norbert Schuff and Foroud, {Tatiana M.} and Kwangsik Nho and Farlow, {Martin R.} and Hake, {Ann Marie} and Matthews, {Brandy R.}",
year = "2019",
month = "12",
day = "1",
doi = "10.1038/s41467-019-10945-z",
language = "English (US)",
volume = "10",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - Non-coding variability at the APOE locus contributes to the Alzheimer’s risk

AU - Alzheimer’s Disease Neuroimaging Initiative

AU - Zhou, Xiaopu

AU - Chen, Yu

AU - Mok, Kin Y.

AU - Kwok, Timothy C.Y.

AU - Mok, Vincent C.T.

AU - Guo, Qihao

AU - Ip, Fanny C.

AU - Chen, Yuewen

AU - Mullapudi, Nandita

AU - Weiner, Michael W.

AU - Aisen, Paul

AU - Petersen, Ronald

AU - Jack, Clifford R.

AU - Jagust, William

AU - Trojanowski, John Q.

AU - Toga, Arthur W.

AU - Beckett, Laurel

AU - Green, Robert C.

AU - Saykin, Andrew J.

AU - Morris, John

AU - Shaw, Leslie M.

AU - Khachaturian, Zaven

AU - Sorensen, Greg

AU - Kuller, Lew

AU - Raichle, Marcus

AU - Paul, Steven

AU - Davies, Peter

AU - Fillit, Howard

AU - Hefti, Franz

AU - Holtzman, David

AU - Mesulam, Marek M.

AU - Potter, William

AU - Snyder, Peter

AU - Schwartz, Adam

AU - Montine, Tom

AU - Thomas, Ronald G.

AU - Donohue, Michael

AU - Walter, Sarah

AU - Gessert, Devon

AU - Sather, Tamie

AU - Jiminez, Gus

AU - Harvey, Danielle

AU - Bernstein, Matthew

AU - Thompson, Paul

AU - Schuff, Norbert

AU - Foroud, Tatiana M.

AU - Nho, Kwangsik

AU - Farlow, Martin R.

AU - Hake, Ann Marie

AU - Matthews, Brandy R.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Alzheimer’s disease (AD) is a leading cause of mortality in the elderly. While the coding change of APOE-ε4 is a key risk factor for late-onset AD and has been believed to be the only risk factor in the APOE locus, it does not fully explain the risk effect conferred by the locus. Here, we report the identification of AD causal variants in PVRL2 and APOC1 regions in proximity to APOE and define common risk haplotypes independent of APOE-ε4 coding change. These risk haplotypes are associated with changes of AD-related endophenotypes including cognitive performance, and altered expression of APOE and its nearby genes in the human brain and blood. High-throughput genome-wide chromosome conformation capture analysis further supports the roles of these risk haplotypes in modulating chromatin states and gene expression in the brain. Our findings provide compelling evidence for additional risk factors in the APOE locus that contribute to AD pathogenesis.

AB - Alzheimer’s disease (AD) is a leading cause of mortality in the elderly. While the coding change of APOE-ε4 is a key risk factor for late-onset AD and has been believed to be the only risk factor in the APOE locus, it does not fully explain the risk effect conferred by the locus. Here, we report the identification of AD causal variants in PVRL2 and APOC1 regions in proximity to APOE and define common risk haplotypes independent of APOE-ε4 coding change. These risk haplotypes are associated with changes of AD-related endophenotypes including cognitive performance, and altered expression of APOE and its nearby genes in the human brain and blood. High-throughput genome-wide chromosome conformation capture analysis further supports the roles of these risk haplotypes in modulating chromatin states and gene expression in the brain. Our findings provide compelling evidence for additional risk factors in the APOE locus that contribute to AD pathogenesis.

UR - http://www.scopus.com/inward/record.url?scp=85070600884&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85070600884&partnerID=8YFLogxK

U2 - 10.1038/s41467-019-10945-z

DO - 10.1038/s41467-019-10945-z

M3 - Article

C2 - 31346172

AN - SCOPUS:85070600884

VL - 10

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 3310

ER -