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Identification of novel Alzheimer’s disease genes co-expressed with TREM2

View ORCID ProfileJoseph S. Reddy, Mariet Allen, Xue Wang, Joanna M. Biernacka, Brandon J. Coombes, Gregory D. Jenkins, Jason P. Sinnwell, Minerva M. Carrasquillo, Cyril P. Pottier, Yingxue Ren, Vivekananda Sarangi, Curtis S. Younkin, Yan W. Asmann, Owen A. Ross, Rosa Rademakers, Todd E. Golde, Nilüfer Ertekin-Taner, Steven G. Younkin
doi: https://doi.org/10.1101/2020.11.13.381640
Joseph S. Reddy
1Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, 32224, USA
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Mariet Allen
2Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA
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Xue Wang
1Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, 32224, USA
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Joanna M. Biernacka
3Department of Health Sciences Research, Mayo Clinic, Rochester, MN, 55905, USA
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Brandon J. Coombes
3Department of Health Sciences Research, Mayo Clinic, Rochester, MN, 55905, USA
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Gregory D. Jenkins
3Department of Health Sciences Research, Mayo Clinic, Rochester, MN, 55905, USA
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Jason P. Sinnwell
3Department of Health Sciences Research, Mayo Clinic, Rochester, MN, 55905, USA
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Minerva M. Carrasquillo
2Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA
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Cyril P. Pottier
2Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA
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Yingxue Ren
1Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, 32224, USA
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Vivekananda Sarangi
3Department of Health Sciences Research, Mayo Clinic, Rochester, MN, 55905, USA
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Curtis S. Younkin
4Department of Information Technology, Mayo Clinic, Jacksonville, FL 32224, USA
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Yan W. Asmann
1Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, 32224, USA
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Owen A. Ross
2Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA
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Rosa Rademakers
2Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA
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Todd E. Golde
6Department of Neuroscience and Neurology, University of Florida, Gainesville, Florida 32611, USA
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Nilüfer Ertekin-Taner
2Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA
5Department of Neurology, Mayo Clinic, Jacksonville, FL, 32224, USA
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Steven G. Younkin
2Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA
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  • For correspondence: Younkin.Steven@mayo.edu
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Abstract

By analyzing whole-exome data from the Alzheimer’s disease sequencing project (ADSP), we identify a set of 4 genes that show highly significant association with Alzheimer’s disease (AD). These genes were identified within a human TREM2 co-expression network using a novel approach wherein prioritized polygenic score analyses were performed sequentially to identify significant polygenic components. Two of the 4 genes (TREM2, RIN3) have previously been linked to AD and two (ATP8B4, IL17RA) are novel. Like TREM2, the 2 novel AD genes are selectively expressed in human microglial cells. The most significant variants in ATP8B4 and IL17RA are non-synonymous variants with strong effects comparable to the APOE ε4 and ε2 alleles. These protein-altering variants will provide unique opportunities to further explore the biological role of microglial cells in AD and help inform future immune modulatory therapeutic development for AD.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted November 15, 2020.
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Identification of novel Alzheimer’s disease genes co-expressed with TREM2
Joseph S. Reddy, Mariet Allen, Xue Wang, Joanna M. Biernacka, Brandon J. Coombes, Gregory D. Jenkins, Jason P. Sinnwell, Minerva M. Carrasquillo, Cyril P. Pottier, Yingxue Ren, Vivekananda Sarangi, Curtis S. Younkin, Yan W. Asmann, Owen A. Ross, Rosa Rademakers, Todd E. Golde, Nilüfer Ertekin-Taner, Steven G. Younkin
bioRxiv 2020.11.13.381640; doi: https://doi.org/10.1101/2020.11.13.381640
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Identification of novel Alzheimer’s disease genes co-expressed with TREM2
Joseph S. Reddy, Mariet Allen, Xue Wang, Joanna M. Biernacka, Brandon J. Coombes, Gregory D. Jenkins, Jason P. Sinnwell, Minerva M. Carrasquillo, Cyril P. Pottier, Yingxue Ren, Vivekananda Sarangi, Curtis S. Younkin, Yan W. Asmann, Owen A. Ross, Rosa Rademakers, Todd E. Golde, Nilüfer Ertekin-Taner, Steven G. Younkin
bioRxiv 2020.11.13.381640; doi: https://doi.org/10.1101/2020.11.13.381640

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