Identification of novel Alzheimer’s disease genes co-expressed withTREM2

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.

Network approaches for omics studies of neurodegenerative diseases

“…They identified significant gene-gene interactions associated with AD that were involved in networks of cholesterol metabolism, βamyloid (Aβ) metabolism, inflammation, oxidative stress, and others. More recently, Reddy et al (2020) analyzed close to ten thousand whole exomes from the Alzheimer's Disease Sequencing Project and used polygenic risk scores to combine single nucleotide variant analysis with co-expression network analysis to identify four genes significantly associated with AD within a co-expression network with TREM2. Another recent study combined epistasis screening with co-expression network analysis using multiple independent datasets and identified two significant genetic interactions implicated in AD (Wang et al, 2021).…”