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

doi:10.1038/s41467-019-10945-z

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

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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 language	English
Article number	3310
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-10945-z
State	Published - Dec 1 2019

Bibliographical note

Funding Information:
We thank Dr. Yu Pong Ng, Dr. Kwok Wang Hung, Ka Chun Lok, Cara Kwong, Yuling Zhang, Saijuan Liu, Shuangshuang Ma, Yan Ma, and Chi Wai Ng for their excellent technical assistance, as well as other members of the Ip laboratory for many helpful discussions. This study was supported in part by the National Basic Research Program of China (973 Program; 2013CB530900), the Hong Kong Research Grants Council Theme-based Research Scheme (T13-607/12R), the General Research Fund (grant number GRF CUHK 471911), the Area of Excellence Scheme of the University Grants Committee (AoE/M-604/16), Innovation Technology Commission (ITS/393/15FP and ITCPD/17-9), the National Natural Science Foundation of China (31671047 and 31400923), the National Key R&D Program of China (SQ2018YFE020417, 2017YFE0190000), the Guangdong Provincial Key S&T Program (2018B030336001), and the Shenzhen Knowledge Innovation Program (JCYJ20151030140325152, JCYJ20170413173717055, JCYJ20151030154629774, JCYJ20170413165053031, and JCYJ20160428145818099). X.Z. was a recipient of the Hing Kee Java Edible Bird’s Nest (HKJEBN) Company Limited Scholarship for Health and Quality Living. Please refer to the Supplementary Notes 1 and 2 for corresponding acknowledgments for the ADNI dataset, Alzheimer’s Disease Genetics Consortium (ADGC) Genome Wide Association Study–NIA Alzheimer’s Disease Centers Cohort (ADC dataset, the National Institute on Aging–Late Onset Alzheimer’s Disease Family Study (LOAD dataset), funding support for the “Genetic Consortium for Late Onset Alzheimer’s Disease”, the Genotype-Tissue Expression (GTEx) Project and the CommonMind dataset. Part of the data used in the preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in the analysis or writing of this report. A complete listing of ADNI investigators can be found in the Supplementary Note and at the following URL: [http://adni.loni.usc.edu/ wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf].

Publisher Copyright:
© 2019, The Author(s).

ASJC Scopus subject areas

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-019-10945-z

Cite this

@article{14d5cd223aeb4a2ca669eed0bbbc3809,

title = "Non-coding variability at the APOE locus contributes to the Alzheimer{\textquoteright}s risk",

abstract = "Alzheimer{\textquoteright}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 = "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 Bret Borowski and Jeff Gunter and Matt Senjem and Greg Jicha and Richard King",

note = "Funding Information: We thank Dr. Yu Pong Ng, Dr. Kwok Wang Hung, Ka Chun Lok, Cara Kwong, Yuling Zhang, Saijuan Liu, Shuangshuang Ma, Yan Ma, and Chi Wai Ng for their excellent technical assistance, as well as other members of the Ip laboratory for many helpful discussions. This study was supported in part by the National Basic Research Program of China (973 Program; 2013CB530900), the Hong Kong Research Grants Council Theme-based Research Scheme (T13-607/12R), the General Research Fund (grant number GRF CUHK 471911), the Area of Excellence Scheme of the University Grants Committee (AoE/M-604/16), Innovation Technology Commission (ITS/393/15FP and ITCPD/17-9), the National Natural Science Foundation of China (31671047 and 31400923), the National Key R&D Program of China (SQ2018YFE020417, 2017YFE0190000), the Guangdong Provincial Key S&T Program (2018B030336001), and the Shenzhen Knowledge Innovation Program (JCYJ20151030140325152, JCYJ20170413173717055, JCYJ20151030154629774, JCYJ20170413165053031, and JCYJ20160428145818099). X.Z. was a recipient of the Hing Kee Java Edible Bird{\textquoteright}s Nest (HKJEBN) Company Limited Scholarship for Health and Quality Living. Please refer to the Supplementary Notes 1 and 2 for corresponding acknowledgments for the ADNI dataset, Alzheimer{\textquoteright}s Disease Genetics Consortium (ADGC) Genome Wide Association Study–NIA Alzheimer{\textquoteright}s Disease Centers Cohort (ADC dataset, the National Institute on Aging–Late Onset Alzheimer{\textquoteright}s Disease Family Study (LOAD dataset), funding support for the “Genetic Consortium for Late Onset Alzheimer{\textquoteright}s Disease”, the Genotype-Tissue Expression (GTEx) Project and the CommonMind dataset. Part of the data used in the preparation of this article were obtained from the Alzheimer{\textquoteright}s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in the analysis or writing of this report. A complete listing of ADNI investigators can be found in the Supplementary Note and at the following URL: [http://adni.loni.usc.edu/ wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf]. Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41467-019-10945-z",

language = "English",

volume = "10",

number = "1",

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TY - JOUR

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

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 - Borowski, Bret

AU - Gunter, Jeff

AU - Senjem, Matt

AU - Jicha, Greg

AU - King, Richard

N1 - Funding Information: We thank Dr. Yu Pong Ng, Dr. Kwok Wang Hung, Ka Chun Lok, Cara Kwong, Yuling Zhang, Saijuan Liu, Shuangshuang Ma, Yan Ma, and Chi Wai Ng for their excellent technical assistance, as well as other members of the Ip laboratory for many helpful discussions. This study was supported in part by the National Basic Research Program of China (973 Program; 2013CB530900), the Hong Kong Research Grants Council Theme-based Research Scheme (T13-607/12R), the General Research Fund (grant number GRF CUHK 471911), the Area of Excellence Scheme of the University Grants Committee (AoE/M-604/16), Innovation Technology Commission (ITS/393/15FP and ITCPD/17-9), the National Natural Science Foundation of China (31671047 and 31400923), the National Key R&D Program of China (SQ2018YFE020417, 2017YFE0190000), the Guangdong Provincial Key S&T Program (2018B030336001), and the Shenzhen Knowledge Innovation Program (JCYJ20151030140325152, JCYJ20170413173717055, JCYJ20151030154629774, JCYJ20170413165053031, and JCYJ20160428145818099). X.Z. was a recipient of the Hing Kee Java Edible Bird’s Nest (HKJEBN) Company Limited Scholarship for Health and Quality Living. Please refer to the Supplementary Notes 1 and 2 for corresponding acknowledgments for the ADNI dataset, Alzheimer’s Disease Genetics Consortium (ADGC) Genome Wide Association Study–NIA Alzheimer’s Disease Centers Cohort (ADC dataset, the National Institute on Aging–Late Onset Alzheimer’s Disease Family Study (LOAD dataset), funding support for the “Genetic Consortium for Late Onset Alzheimer’s Disease”, the Genotype-Tissue Expression (GTEx) Project and the CommonMind dataset. Part of the data used in the preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in the analysis or writing of this report. A complete listing of ADNI investigators can be found in the Supplementary Note and at the following URL: [http://adni.loni.usc.edu/ wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf]. Publisher Copyright: © 2019, The Author(s).

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.

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U2 - 10.1038/s41467-019-10945-z

DO - 10.1038/s41467-019-10945-z

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ER -

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

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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