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Summary Human Genetics Mechanistic Insight Relevance To Non-Coding Genetic Analysis Implicates IL18RAP 3′UTR in ALS Chen Eitan1, Elad Barkan1, Tsviya Olender1, Aviad Siany1, Natalia Rivkin1, Hagai Marmor-Kollet1, Kristel R. van Eijk2, Matthieu Moisse3, Sali M. K. Farhan4, Shu-Ting Hung5, Yael Alon1, Nancy Yacovzada1, Johnathan Cooper-Knock6, Kevin P. Kenna2, Rick A. A. van der Spek2, William Sproviero7, Ahmad Al Khleifat7, Alfredo Iacoangeli7, Elik Chapnik1, Daphna Rothschild1, Omer Weissbrod1, Sebastian Werneburg8, Dorothy P. Schafer8, Robert H. Brown Jr8, Pamela J. Shaw7, Philip Van Damme3, Leonard H. van den Berg2, Hemali P. Phatnani9, Eran Segal1, Justin K. Ichida5, Ammar Al-Chalabi7, Jan H. Veldink2, Project MinE ALS Sequencing Consortium, NYGC ALS Consortium and Eran Hornstein1* 1Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel; 2Department of Neurology, UMC Utrecht Brain Center, Utrecht, The Netherlands; 3KU Leuven - University of Leuven, Department of Neurosciences, Leuven, Belgium; 4Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; 5Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, Los Angeles, CA, USA; 6Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, UK; 7King's College London, Maurice Wohl Clinical Neuroscience Institute, London, UK; 8Department of Neurobiology, University of Massachusetts Medical School, Worcester, MA, USA; 9Center for Genomics of Neurodegenerative Disease, New York Genome Center. 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. Human Genetics Mechanistic Insight Relevance to ALS Region-based rare-variant association analysis identified IL18RAP 3′UTR variants Functional validation of IL18RAP Variants IL18RAP 3'UTR variant ameliorates *** disease in C9orf72 patient iMNs significantly enriched in non-ALS genomes ** ** ** and in patients with ALS 3.5 *** ** ** *** 1.5 3.0 2.5 1.0 2.0 1.5 1.0 0.5 0.5 IL18RAP/Tubulin [a.u] IL18RAP/Tubulin 0.0 0.0 Relative IL18RAP expression IL18RAP Relative sALS sALS sALS sALS Control Control Control Control IL18RAP 3'UTR IL18RAP 3'UTR variants - + variants - + IL18RAP 3’UTR protective variants significantly reduce IL18RAP expression IL18RAP 3’UTR variant attenuates IL-18 / NF-κB signaling Mutant IL18RAP 3’UTR is protective in human patients with ALS (A) Region-based rare-variant association analysis was performed on rare (MAF ≤0.01) qualifying variants in: (i) 295 candidate protein-coding genes encoding for ALS-relevant proteins or proteins associated with miRNA biogenesis/activity. Variants were included if predicted to be deleterious; (ii) variants abrogating or gaining miRNA recognition elements in 3′UTRs of the 295 genes; (iii) all known pre-miRNA genes in the human genome; and (iv) predicted networks, comprised of aggregated variants detected in a specific mature miRNA sequence and its cognate down-stream 3’UTR targets. (B) QQ plot of obtained and expected P-values for the burden of rare variants (log scale) gained by collapsed region-based association analysis of all genomic regions described in (A). Survival tracking microscopy of Hb9::RFP+ iMNs, transduced with IL18RAP lentiviruses, after neurotrophic factors withdrawal and introduction of IL-18 (A). Kaplan-Meier survival plots for control Genome-wide analysis of all known human 3’UTRs Rare IL18RAP 3′UTR variants are depleted in an (CTRL) and C9orf72 patient (C9-ALS) iMNs, transduced with IL18RAP lentiviruses (WT/V3/3CDS). Traces of iMNs from 2 donors per genotype. Log-rank test for the entire survival time course (B-D). independent ALS cohort NF-κB reporter assay in U2OS cell line transfected with wild-type (WT) IL18RAP, IL18RAP harboring IL18RAP variant is associated with delayed age of death (+6.1 years, 9/4263) (E) and age of diagnosis variants in the 3’UTR (V3, V1) or an IL18RAP dominant negative coding mutant (3CDS) vectors. (+6.2 years, 8/4216) (F), relative to the mean age of all Project MinE and NYGC ALS patients. Summary IL18RAP 3′UTR is the most significant We devised a method for identifying rare qualifying variants in non-coding genomic regions. 3’UTR associated with ALS We performed an unbiased genetic study of miRNAs and 3’UTRs using Project MinE’s large-scale WGS data. Region-based burden analysis identified rare IL18RAP 3′UTR variants significantly enriched in non-ALS genomes and associate with a five-fold reduced risk of developing ALS. Carriers have 5 times less ALS risk IL18RAP 3′UTR variants modify NF-κB signaling, provide survival advantage for cultured ALS motor neurons and ALS patients, and highlight its potential protective value..
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