Polygenic risk score analysis identifies deleterious protein-coding variants in novel immune pathway genesATP8B4, FCGR1A, andLILRB1that associate with Alzheimer’s disease

Background Alterations in innate immunity are pathologically associated with and genetically implicated in Alzheimer’s disease (AD). In the whole exome sequence (WES) dataset generated by the Alzheimer’s Disease Sequencing Project (ADSP), only the previously identified p.R47H variant in the innate immunity gene, TREM2 , shows study-wide association with risk of AD. Using a novel approach, we searched the ADSP WES data to identify additional immune pathway genes with deleterious variants that, like TREM2 .pR47H, show strong association with AD. Methods Using polygenic risk scores (PRS) to analyze association with AD, we evaluated deleterious variants (CADD Phred-scaled score > 20) with a minor allele count of 20 or more in 228 genes comprising an immune co-expression network containing TREM2 (CEN TREM2 ). A significant polygenic component composed of deleterious stop-gain and non-synonymous variants was identified, and false discovery rates were determined for the variants in this component. In genes harboring a significant variant, PRS for all variants in the genes were then analyzed. Results The PRS for the 182 deleterious variants in CEN TREM2 showed significant association with AD that was driven by 142 deleterious variants (136 non-synonymous, 6 stop-gain). In the 142 variant polygenic component, four variants had significant AD risk association: TREM2 .pR47H, two deleterious stop-gain variants ( FCGR1A .pR92X, and LILRB1 .pY331X) in novel AD genes and 1 non-synonymous variant (ATP8B4 .pG395S). Remarkably, PRS for the 36 additional variants in these four genes also showed significant association with AD. The PRS for all 40 variants in the 4 genes, showed significant, replicable association with AD and 3 additional variants in this polygenic component had significant false discovery rates: ATP8B4 .pR1059Q, LILRB1 .pP7P, and LILRB1 .pY327Y. Conclusions Here, we identify 3 immune pathway genes ( ATP8B4, LILRB1 , and FCGR1A ) with a variant that associates with AD. Like TREM2 .pR47H, each of the variants has a minor allele frequency less than 1% and is a deleterious, protein altering variant with a strong effect that increases or decreases ( LILRB1 .pY331X) risk of AD. Additional variants in these genes also alter risk of AD. The variants identified here are ideally suited for studies aimed at understanding how the innate immune system may be modulated to alter risk of AD.