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