Non-Coding Genetic Analysis Implicates Interleukin 18 Receptor Accessory Protein 3'UTR in Amyotrophic Lateral Sclerosis
Eitan, C.; Barkan, E.; Olender, T.; van Eijk, K. R.; Moisse, M.; Farhan, S. M. K.; Siany, A.; Hung, S.-T.; Yacovzada, N.; Cooper-Knock, J.; Kenna, K. P.; van der Spek, R. A. A.; Sproviero, W.; Al Khleifat, A.; Iacoangeli, A.; Shatunov, A. S.; Jones, A. R.; Chapnik, E.; Rothschild, D.; Weissbrod, O.; Werneburg, S.; Schafer, D. P.; Brown, R. H.; Shaw, P. J.; Van Damme, P.; van den Berg, L. H.; Phatnani, H. P.; Segal, E.; Ichida, J. K.; Al-Chalabi, A.; Veldink, J. H.; Project MinE ALS Sequencing Consortium, ; NYGC ALS Consortium, ; Hornstein, E.
Show abstract
The non-coding genome is substantially larger than the protein-coding genome but is largely unexplored by genetic association studies. Here, we performed region-based burden analysis of >25,000 variants in untranslated regions of 6,139 amyotrophic lateral sclerosis (ALS) whole-genomes and 70,403 non-ALS controls. We identified Interleukin-18 Receptor Accessory Protein (IL18RAP) 3'UTR variants significantly enriched in non-ALS genomes, replicated in an independent cohort, and associated with a five-fold reduced risk of developing ALS. Variant IL18RAP 3'UTR reduces mRNA stability and the binding of RNA-binding proteins. Variant IL18RAP 3'UTR further dampens neurotoxicity of human iPSC-derived C9orf72-ALS microglia that depends on NF-{kappa}B signaling. Therefore, the variant IL18RAP 3'UTR provides survival advantage for motor neurons co-cultured with C9-ALS microglia. The study reveals direct genetic evidence and therapeutic targets for neuro-inflammation, and emphasizes the importance of non-coding genetic association studies. One Sentence SummaryNon-coding genetic variants in IL-18 receptor 3UTR decrease ALS risk by modifying IL-18-NF-{kappa}B signaling in microglia.
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