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

Eitan, Chen; Siany, Aviad; Barkan, Elad; Olender, Tsviya; van Eijk, Kristel; Moisse, Matthieu; Farhan, Sali; Danino, Yehuda; Yanowski, Eran; Marmor-Kollet, Hagai; Rivkin, Natalia; Yacovzada, Nancy; Hung, Shu-Ting; Cooper-Knock, Johnathan; Yu, Chien-Hsiung; Louis, Cynthia; Masters, Seth; Kenna, Kevin; van der Spek, Rick; Sproviero, William; Al Khleifat, Ahmad; Iacoangeli, Alfredo; Shatunov, Aleksey; Jones, Ashley; Elbaz-Alon, Yael; Cohen, Yahel; Chapnik, Elik; Rothschild, Daphna; Weissbrod, Omer; Beck, Gilad; Ainbinder, Elena; Ben-Dor, Shifra; Werneburg, Sebastian; Schafer, Dorothy; Brown, Robert; Shaw, Pamela; Van Damme, Philip; van den Berg, Leonard; Phatnani, Hemali; Segal, Eran; Ichida, Justin; Al-Chalabi, Ammar; Veldink, Jan; Hornstein, Eran; Project MinE ALS Sequencing Consortium,; NYGC ALS Consortium,

doi:10.1101/2021.06.03.446863

Author:

Eitan, Chen

Siany, Aviad ; Barkan, Elad ; Olender, Tsviya ; van Eijk, Kristel ; Moisse, Matthieu ; Farhan, Sali ; Danino, Yehuda ; Yanowski, Eran ; Marmor-Kollet, Hagai ; Rivkin, Natalia ; Yacovzada, Nancy ; Hung, Shu-Ting ; Cooper-Knock, Johnathan ; Yu, Chien-Hsiung ; Louis, Cynthia ; Masters, Seth ; Kenna, Kevin ; van der Spek, Rick ; Sproviero, William ; Al Khleifat, Ahmad ; Iacoangeli, Alfredo ; Shatunov, Aleksey ; Jones, Ashley ; Elbaz-Alon, Yael ; Cohen, Yahel ; Chapnik, Elik ; Rothschild, Daphna ; Weissbrod, Omer ; Beck, Gilad ; Ainbinder, Elena ; Ben-Dor, Shifra ; Werneburg, Sebastian ; Schafer, Dorothy ; Brown, Robert ; Shaw, Pamela ; Van Damme, Philip ; van den Berg, Leonard ; Phatnani, Hemali ; Segal, Eran ; Ichida, Justin ; Al-Chalabi, Ammar ; Veldink, Jan ; Hornstein, Eran ; Project MinE ALS Sequencing Consortium, ; NYGC ALS Consortium,

Keywords:

NYGC ALS Consortium, Project MinE ALS Sequencing Consortium

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-κB 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 Summary

Non-coding genetic variants in IL-18 receptor 3’UTR decrease ALS risk by modifying IL-18-NF-κB signaling in microglia.