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

Authors

Xiaopu Zhou, Hong Kong University of Science and Technology
Yu Chen, Hong Kong University of Science and Technology
Kin Y. Mok, Hong Kong University of Science and Technology
Timothy C.Y. Kwok, Chinese University of Hong Kong
Vincent C.T. Mok, Chinese University of Hong Kong
Qihao Guo, Huashan Hospital
Fanny C. Ip, Hong Kong University of Science and Technology
Yuewen Chen, Hong Kong University of Science and Technology
Nandita Mullapudi, Hong Kong University of Science and Technology
Michael W. Weiner, University of California, San Francisco
Paul Aisen, University of California, San Diego
Ronald Petersen, Mayo Clinic
Clifford R. Jack, Mayo Clinic
William Jagust, University of California, Berkeley
John Q. Trojanowski, University of Pennsylvania
Arthur W. Toga, University of Southern California
Laurel Beckett, University of California, Davis
Robert C. Green, Brigham and Women's Hospital
Andrew J. Saykin, Indiana University Bloomington
John Morris, Washington University in St. Louis
Leslie M. Shaw, University of Pennsylvania
Zaven Khachaturian, University of California, Davis
Greg Sorensen, Siemens AG
Lew Kuller, University of Pittsburgh
Marcus Raichle, Washington University in St. Louis
Steven Paul, Weill Cornell Medicine
Peter Davies, Albert Einstein College of Medicine of Yeshiva University
Howard Fillit, AD Drug Discovery Foundation
Franz Hefti, Acumen Pharmaceuticals
David Holtzman, Washington University in St. Louis
Marek M. Mesulam, Northwestern University
William Potter, National Institute of Mental Health (NIMH)

Document Type

Article

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.

Publication Date

12-1-2019

Publication Title

Nature Communications

E-ISSN

20411723

Volume

10

Issue

1

PubMed ID

31346172

Digital Object Identifier (DOI)

10.1038/s41467-019-10945-z

Recommended Citation

Zhou, Xiaopu; Chen, Yu; Mok, Kin Y.; Kwok, Timothy C.Y.; Mok, Vincent C.T.; Guo, Qihao; Ip, Fanny C.; Chen, Yuewen; Mullapudi, Nandita; Weiner, Michael W.; Aisen, Paul; Petersen, Ronald; Jack, Clifford R.; Jagust, William; Trojanowski, John Q.; Toga, Arthur W.; Beckett, Laurel; Green, Robert C.; Saykin, Andrew J.; Morris, John; Shaw, Leslie M.; Khachaturian, Zaven; Sorensen, Greg; Kuller, Lew; Raichle, Marcus; Paul, Steven; Davies, Peter; Fillit, Howard; Hefti, Franz; Holtzman, David; Mesulam, Marek M.; and Potter, William, "Non-coding variability at the APOE locus contributes to the Alzheimer’s risk" (2019). Neurology. 965.
https://scholar.barrowneuro.org/neurology/965