Non-Coding Genetic Analysis Implicates Interleukin 18 Receptor Accessory Protein 3’UTR in Amyotrophic Lateral Sclerosis

Abstract

The non-coding genome is substantially larger than the protein-coding genome, but the lack of appropriate methodologies for identifying functional variants limits genetic association studies. Here, we developed analytical tools to identify rare variants in pre-miRNAs, miRNA recognition elements in 3’UTRs, and miRNA-target networks. Region-based burden analysis of >23,000 variants in 6,139 amyotrophic lateral sclerosis (ALS) whole-genomes and 70,403 non-ALS controls identified Interleukin-18 Receptor Accessory Protein (IL18RAP) 3’UTR variants significantly enriched in non-ALS genomes, replicate in an independent cohort and associate with a five-fold reduced risk of developing ALS. IL18RAP 3’UTR variants modify NF-κB signaling, provide survival advantage for cultured ALS motor neurons and ALS patients, and reveal direct genetic evidence and therapeutic targets for neuro-inflammation. This systematic analysis of the non-coding genome and specifically miRNA-networks will increase the power of genetic association studies and uncover mechanisms of neurodegeneration. One Sentence Summary Non-coding genetics demonstrate rare variants in IL-18 receptor 3’UTR that modifies ALS risk and progression.