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.

doi:10.1101/2021.06.03.446863

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bioRxiv · 10.1101/2021.06.03.446863

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

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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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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.. 2021-06-05. Non-Coding Genetic Analysis Implicates Interleukin 18 Receptor Accessory Protein 3'UTR in Amyotrophic Lateral Sclerosis. https://doi.org/10.1101/2021.06.03.446863

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