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 Eliot Golde; Nilüfer Ertekin‐Taner; Steven G. Younkin

doi:10.1101/2020.11.13.381640

GeneticsbioRxivNov 13, 2020

Preprint

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

Joseph S. Reddy iD, Mariet Allen iD, Xue Wang iD, Joanna M. Biernacka iD, Brandon J. Coombes iD, Gregory D. Jenkins iD, Jason P. Sinnwell iD, Minerva M. Carrasquillo iD, Cyril P. Pottier iD, Yingxue Ren iD, Vivekananda Sarangi iD, Curtis S. Younkin, Yan W. Asmann iD, Owen A. Ross iD, Rosa Rademakers iD, Todd Eliot Golde iD, Nilüfer Ertekin‐Taner iD, Steven G. Younkin iD

Abstract

By analyzing whole-exome data from the Alzheimers disease sequencing project (ADSP), we identify a set of 4 genes that show highly significant association with Alzheimers 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 {varepsilon}4 and {varepsilon}2 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.

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