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

Alzheimers Dement. 2022 Oct;18(10):1846-1867. doi: 10.1002/alz.12507. Epub 2021 Dec 17.

Authors

Chen Ming^{1

2

3}, Minghui Wang^{1

2

3}, Qian Wang^{1

2

3}, Ryan Neff^{1

2

3}, Erming Wang^{1

2

3}, Qi Shen^{1

2

3}, Joseph S Reddy⁴, Xue Wang⁴, Mariet Allen⁵, Nilüfer Ertekin-Taner^{5

6}, Philip L De Jager^{7

8}, David A Bennett⁹, Vahram Haroutunian^{10

11

12

13}, Eric Schadt^{1

2}, Bin Zhang^{1

2

3}

Affiliations

¹ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
² Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
³ Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
⁴ Department of Quantitative Health Sciences, Mayo Clinic Florida, Jacksonville, Florida, USA.
⁵ Department of Neuroscience, Mayo Clinic Florida, Jacksonville, Florida, USA.
⁶ Department of Neurology, Mayo Clinic Florida, Jacksonville, Florida, USA.
⁷ Center for Translational & Computational Neuroimmunology, Department of Neurology and the Taub Institute, Columbia University Medical Center, New York, New York, USA.
⁸ The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
⁹ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA.
¹⁰ Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹¹ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹² Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, New York.
¹³ Psychiatry, JJ Peters VA Medical Center, Bronx, New York, USA.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Alzheimer Disease* / genetics
DNA Copy Number Variations* / genetics
Humans
RNA, Messenger
Whole Genome Sequencing

Substances

RNA, Messenger

Abstract

Publication types

MeSH terms

Substances

Grants and funding