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 Asmann, Owen A. Ross, Rosa Rademakers, Todd E. Golde, Nilufer Taner, Steven G. Younkin, George M. Eisenberg

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
JournalUnknown Journal
DOIs
StatePublished - Nov 15 2020

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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