@article{7b6e913baa6a470393187de98715a681,
title = "Whole genome sequencing–based copy number variations reveal novel pathways and targets in Alzheimer's disease",
abstract = "Introduction: A few copy number variations (CNVs) have been reported for Alzheimer's disease (AD). However, there is a lack of a systematic investigation of CNVs in AD based on whole genome sequencing (WGS) data. Methods: We used four methods to identify consensus CNVs from the WGS data of 1,411 individuals and further investigated their functional roles in AD using the matched transcriptomic and clinicopathological data. Results: We identified 3,012 rare AD-specific CNVs whose residing genes are enriched for cellular glucuronidation and neuron projection pathways. Genes whose mRNA expressions are significantly correlated with common CNVs are involved in major histocompatibility complex class II receptor activity. Integration of CNVs, gene expression, and clinical and pathological traits further pinpoints a key CNV that potentially regulates immune response in AD. Discussion: We identify CNVs as potential genetic regulators of immune response in AD. The identified CNVs and their downstream gene networks reveal novel pathways and targets for AD.",
keywords = "Alzheimer's disease, copy number variation, correlation network, immune response, late-onset Alzheimer's disease, multi-omics integration, regulation of response to external stimulus, whole genomic sequencing",
author = "Chen Ming and Minghui Wang and Qian Wang and Ryan Neff and Erming Wang and Qi Shen and Reddy, {Joseph S.} and Xue Wang and Mariet Allen and Nil{\"u}fer Ertekin-Taner and {De Jager}, {Philip L.} and Bennett, {David A.} and Vahram Haroutunian and Eric Schadt and Bin Zhang",
note = "Funding Information: Chen Ming, Minghui Wang, Qian Wang, Ryan Neff, Erming Wang, Qi Shen, Joseph S. Reddy, and Xue Wang have nothing to disclose. Bin Zhang, Mariet Allen, David A. Bennett, Vahram Haroutunian, and Eric Schadt received support for the present manuscript. Specifically, this manuscript was supported by Bin Zhang{\textquoteleft}s NIH/NIA grants (R01AG046170, RF1AG054014, RF1AG057440, R01AG057907, U01AG052411, R01AG062355, U01AG058635, R01AG068030) and Mariet Allen's grant (U01‐AG046139) as well as NIH grants for David A. Bennett, Vahram Haroutunian, and Eric Schadt. In the past 36 months, Bin Zhang, Minghui Wang, Mariet Allen, Nil{\"u}fer Ertekin‐Taner, Philip L. De Jager, David A. Bennett, Vahram Haroutunian, and Eric Schadt received grants from NIH or foundations. Specifically, Bin Zhang received 21 grants (R01AG046170, RF1AG054014, RF1AG057440, R01AG057907, U01AG052411, R01AG062355, U01AG058635, R01AG068030, R01AG062661, R01AG062355, HHS‐NIH‐NIAID‐BAA2018, R01 MH111679, R01DA043247, R01DK118243, R01DA048279, R56AG058655, R01AG063819, R01D029322, R01DA047880, R01AG062661, R01AG060341, R21AI149013). Mariet Allen received 3 grants (U01‐AG046139, R01‐AG061796, U01‐AG046139, RF1‐AG51504). Nil{\"u}fer Ertekin‐Taner received 7 grants (U01AG046139, RF1AG051504, R01AG061796, P30AG062677, U01AG061359, NHLBI75N92019D00031/75N92019F00125, R01AG050603). Minghui Wang received one grant (1RF1AG066526‐01A1). Philip L. De Jager, David A. Bennett, Vahram Haroutunian, and Eric Schadt received NIH grants. David A. Bennett received a grant from NIH Neurovision. Eric Schadt also received grants from the Helmsley Foundation. None of the co‐authors received royalties or licenses in the past 36 months. In the past 36 months, Philip L. De Jager received consultant fees from Partech, Roche, and Biogen; David A. Bennett received consultant fees from AbbVie, DSMB, Takeda, Origent, and SBIR; Vahram Haroutunian received a consultant fee of $350 from Synaptec; and Eric Schadt is paid by Berg Pharmaceuticals for participation on their scientific advisory board. In the past 36 months, Bin Zhang received an honorarium for presentation from Lehigh University; Nil{\"u}fer Ertekin‐Taner received payments for her presentations at the 15th International Symposium on Geriatrics and Gerontology Inflammation and Dementia: Genomics, System and Therapeutics, Nagoya, Japan; Philip L. De Jager received payments from Novartis, Astra Zeneca, and Biogen for lectures/presentations; David A. Bennett received payments or honoraria from academia in US and government (NGO) for lectures/presentations. In the past 36 months, Bin Zhang received support from FNIH to attend the AMP‐AD program meeting at NIH (the payment was made to him); Minghui Wang received support from FNIH for his travel and hotel lodging for attending NIH project meetings (the payments were made to him); Mariet Allen received a travel fellowship from Alzheimer's Association International Conference for conference registration but without payments, travel reimbursement from Alzheimer's Association, and travel reimbursement from NIH (the payments were made to her); Nil{\"u}fer Ertekin‐Taner received supports for attending the following conferences: 11th ISABS Conference (Split, Croatia), the 15th International Symposium on Geriatrics and Gerontology Inflammation and Dementia: Genomics, System and Therapeutics (Nagoya, Japan), multiple NIH meetings, Department of Neurology, Indiana University School of Medicine (Bloomington, Indiana); David A. Bennett received support for attending meetings from academia in US and government (NGO). In the past 36 months, the following authors have pending patents: Bin Zhang (US2020/056080 titled “STATHMIN 2 (STMN2) as a therapeutic target for Parkinson's disease,” MS‐0029‐01‐US‐P titled “A Novel therapeutic strategy for targeting the molecular subtypes of AD,” and MS‐00‐30‐01‐US‐P titled “Novel Compounds for Treating Alzheimer's Disease”), Minghui Wang (US2020/056080 titled “STATHMIN 2 (STMN2) as a therapeutic target for Parkinson's disease”), Ryan Neff (MS‐0029‐01‐US‐P titled “A Novel therapeutic strategy for targeting the molecular subtypes of AD”). Eric Schadt has patents under consideration relating to novel drug targets and targeting mechanisms for AD, patent applications filed and under review for biomarkers relating to various forms of cancer, predicting drug response and matching to therapies. In the past 36 months, Eric Schadt was on the board of directors for Sema4, a for‐profit company, and for Sage Bionetworks and 4YouAndMe, both non‐profit research institutions; Nil{\"u}fer Ertekin‐Taner was on the external advisory board for the NIH TREAT‐AD consortium; David A. Bennett was on the external advisory board of AbbVie. Funding Information: This study makes use of data generated by the DECIPHER community. A full list of centers that contributed to the generation of the data is available from http://decipher.sanger.ac.uk and via e‐mail from decipher@sanger.ac.uk. Funding for the DECIPHER project was provided by the Wellcome Trust. Dr. Chen Ming would like to thank Dr. Ningyi Shao for all the inspiring discussions. More importantly, Dr. Chen Ming would like to thank her parents for their full support. This paper is to memorialize her dad, who passed away in the pandemic. Publisher Copyright: {\textcopyright} 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.",
year = "2021",
doi = "10.1002/alz.12507",
language = "English (US)",
journal = "Alzheimer's and Dementia",
issn = "1552-5260",
publisher = "Elsevier Inc.",
}