Locus specific endogenous retroviral expression associated with Alzheimer's disease

Tyson Dawson; Uzma Rentia; Jessie Sanford; Carlos Cruchaga; John S K Kauwe; Keith A Crandall

doi:10.3389/fnagi.2023.1186470

Locus specific endogenous retroviral expression associated with Alzheimer's disease

Front Aging Neurosci. 2023 Jul 6:15:1186470. doi: 10.3389/fnagi.2023.1186470. eCollection 2023.

Authors

Tyson Dawson^#^{1

2}, Uzma Rentia^#¹, Jessie Sanford³, Carlos Cruchaga³, John S K Kauwe⁴, Keith A Crandall^{1

2}

Affiliations

¹ Computational Biology Institute, The George Washington University, Washington, DC, United States.
² Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, The George Washington University, Washington, DC, United States.
³ Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States.
⁴ Department of Biology, Brigham Young University, Provo, UT, United States.

^# Contributed equally.

Abstract

Introduction: Human endogenous retroviruses (HERVs) are transcriptionally-active remnants of ancient retroviral infections that may play a role in Alzheimer's disease.

Methods: We combined two, publicly available RNA-Seq datasets with a third, novel dataset for a total cohort of 103 patients with Alzheimer's disease and 45 healthy controls. We use telescope to perform HERV quantification for these samples and simultaneously perform gene expression analysis.

Results: We identify differentially expressed genes and differentially expressed HERVs in Alzheimer's disease patients. Differentially expressed HERVs are scattered throughout the genome; many of them are members of the HERV-K superfamily. A number of HERVs are correlated with the expression of dysregulated genes in Alzheimer's and are physically proximal to genes which drive disease pathways.

Discussion: Dysregulated expression of ancient retroviral insertions in the human genome are present in Alzheimer's disease and show localization patterns that may explain how these elements drive pathogenic gene expression.

Keywords: Alzheimer’s disease; HERV; RNA-Seq; endogenous retrovirus; gene expression.

Grants and funding

This work was supported by grants from the National Institutes of Health [R01AG044546 (CC), P01AG003991 (CC) RF1AG053303 (CC), RF1AG058501 (CC), U01AG058922 (CC), RF1AG071706 (CC), and R01AG078964 (CC)], the Chan Zuckerberg Initiative (CZI), the Michael J. Fox Foundation (CC), the Department of Defense (LI- W81XWH2010849), and the Alzheimer’s Association Zenith Fellows Award (ZEN-22-848604, awarded to CC), and anonymous foundation. The recruitment and clinical characterization of research participants at Washington University were supported by the NIH P30AG06644, P01AG0399, and P01AG026276. This work was also supported by access to equipment made possible by the Hope Center for Neurological Disorders, the Neurogenomics and Informatics Center (NGI: https://neurogenomics.wustl.edu/) and the Departments of Neurology and Psychiatry at Washington University School of Medicine. The analytical component of this work was partially supported by funding from Brigham Young University.