Whole genome sequencing–based copy number variations reveal novel pathways and targets in Alzheimer's disease

Chen Ming; Minghui Wang; Qian Wang; Ryan Neff; Erming Wang; Qi Shen; Joseph S. Reddy; Xue Wang; Mariet Allen; Nilüfer Ertekin-Taner; Philip L. De Jager; David A. Bennett; Vahram Haroutunian; Eric Schadt; Bin Zhang

doi:10.1002/alz.12507

Whole genome sequencing–based copy number variations reveal novel pathways and targets in Alzheimer's disease

Chen Ming, Minghui Wang, Qian Wang, Ryan Neff, Erming Wang, Qi Shen, Joseph S. Reddy, Xue Wang, Mariet Allen, Nilüfer Ertekin-Taner, Philip L. De Jager, David A. Bennett, Vahram Haroutunian, Eric Schadt, Bin Zhang

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Pages (from-to)	1846-1867
Number of pages	22
Journal	Alzheimer's and Dementia
Volume	18
Issue number	10
DOIs	https://doi.org/10.1002/alz.12507
State	Published - Oct 2022

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

ASJC Scopus subject areas

Epidemiology
Health Policy
Developmental Neuroscience
Clinical Neurology
Geriatrics and Gerontology
Cellular and Molecular Neuroscience
Psychiatry and Mental health

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10.1002/alz.12507

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Ming, C., Wang, M., Wang, Q., Neff, R., Wang, E., Shen, Q., Reddy, J. S., Wang, X., Allen, M., Ertekin-Taner, N., De Jager, P. L., Bennett, D. A., Haroutunian, V., Schadt, E., & Zhang, B. (2022). Whole genome sequencing–based copy number variations reveal novel pathways and targets in Alzheimer's disease. Alzheimer's and Dementia, 18(10), 1846-1867. https://doi.org/10.1002/alz.12507

Ming, C, Wang, M, Wang, Q, Neff, R, Wang, E, Shen, Q, Reddy, JS, Wang, X, Allen, M, Ertekin-Taner, N, De Jager, PL, Bennett, DA, Haroutunian, V, Schadt, E & Zhang, B 2022, 'Whole genome sequencing–based copy number variations reveal novel pathways and targets in Alzheimer's disease', Alzheimer's and Dementia, vol. 18, no. 10, pp. 1846-1867. https://doi.org/10.1002/alz.12507

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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 = "Publisher Copyright: {\textcopyright} 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.",

year = "2022",

month = oct,

doi = "10.1002/alz.12507",

language = "English (US)",

volume = "18",

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AU - Ming, Chen

AU - Wang, Minghui

AU - Wang, Qian

AU - Neff, Ryan

AU - Wang, Erming

AU - Shen, Qi

AU - Reddy, Joseph S.

AU - Wang, Xue

AU - Allen, Mariet

AU - Ertekin-Taner, Nilüfer

AU - De Jager, Philip L.

AU - Bennett, David A.

AU - Haroutunian, Vahram

AU - Schadt, Eric

AU - Zhang, Bin

PY - 2022/10

Y1 - 2022/10

N2 - 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.

AB - 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.

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Whole genome sequencing–based copy number variations reveal novel pathways and targets in Alzheimer's disease

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Keywords

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