Whole genome sequencing reveals that variants in the Interleukin 18 Receptor Accessory Protein 3′UTR protect against ALS. 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. Overall design: 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).