Whole genome sequencing reveals that variants in the Interleukin 18 Receptor Accessory Protein 3′UTR protect against ALS

The non-coding genome is substantially larger than the protein-coding genome, but has been largely unexplored by genetic association studies. Here, we performed region-based rare-variant association analysis of >25,000 variants in untranslated regions of 6,139 amyotrophic lateral sclerosis (ALS) whole-genomes and those of 70,403 non-ALS controls. We identified Interleukin-18 Receptor Accessory Protein (IL18RAP) 3′UTR variants as significantly enriched in non-ALS genomes and associated with five-fold reduced risk of developing ALS, and this was replicated in an independent cohort. These variants in the IL18RAP 3′UTR reduce mRNA stability and the binding of double-stranded RNA-binding proteins. Finally, the variants of IL18RAP 3′UTR confer a survival advantage for motor neurons because they dampen neurotoxicity of human iPSC-derived microglia bearing an ALS-associated expansion in C9orf72, and this depends on NF-κB signaling. This study reveals genetic variants that protect against ALS by reducing neuroinflammation, and emphasizes the importance of non-coding genetic association studies. Transcriptomics comparison in isogenic ipMG harboring variant vs. canonical IL18RAP 3'UTR, following exposure to LPS (100ng/mL) + IL18 (100ng/mL) (n=4 per group).