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

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Non-Coding Genetic Analysis Implicates Interleukin 18 Receptor Accessory Protein 3'UTR in Amyotrophic Lateral Sclerosis bioRxiv preprint doi: https://doi.org/10.1101/2021.06.03.446863; this version posted June 5, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Non-Coding Genetic Analysis Implicates Interleukin 18 Receptor Accessory Protein 3′UTR in Amyotrophic Lateral Sclerosis Authors: Chen Eitan1, Elad Barkan2, Tsviya Olender1, Kristel R. van Eijk3, Matthieu Moisse4,5, Sali M. K. Farhan6,7, Aviad Siany1, Shu-Ting Hung8-10, Nancy Yacovzada1,2, Johnathan Cooper-Knock11, Kevin P. Kenna3, Rick A. A. van der Spek3, William Sproviero12, Ahmad Al Khleifat12, Alfredo Iacoangeli12, Aleksey Shatunov12, Ashley R. Jones12, Elik Chapnik1, Daphna Rothschild2,13,14, Omer Weissbrod2, Sebastian Werneburg15, Dorothy P. Schafer15, Robert H. Brown Jr16, Pamela J. Shaw11, Philip Van Damme4,5,17, Leonard H. van den Berg3, Hemali P. Phatnani18, Eran Segal2, Justin K. Ichida8-10, Ammar Al-Chalabi12,19, Jan H. Veldink3, Project MinE ALS Sequencing Consortium20, NYGC ALS Consortium20 and Eran Hornstein1* Affiliations: 1Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel. 2Department of Computer Science And Applied Math, Weizmann Institute of Science, Rehovot 7610001, Israel. 3Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, 3584 CG, The Netherlands. 4KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology, B-3000 Leuven, Belgium. 5VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, Leuven, Belgium. 6Analytic and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. 7Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. 8Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. 9Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Los Angeles, CA 90033, USA. 10Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA. 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.06.03.446863; this version posted June 5, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 11Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield S10 2HQ, UK. 12King's College London, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology & Neuroscience, De Crespigny Park, London, SE5 8AF, United Kingdom. 13Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA 14Department of Genetics, Stanford University, Stanford, CA 94305, USA 15Department of Neurobiology, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA. 16Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA. 17University Hospitals Leuven, Department of Neurology, Leuven, Belgium. 18Center for Genomics of Neurodegenerative Disease, New York Genome Center. 19King's College Hospital, Denmark Hill, London, SE5 9RS, United Kingdom. 20A list of Consortiums PIs and affiliations appears in the Supplementary Information. *Corresponding author. Tel: +972 89346215; Fax: +972 89342108; E-mail: [email protected] 2 bioRxiv preprint doi: https://doi.org/10.1101/2021.06.03.446863; this version posted June 5, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 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. 3 bioRxiv preprint doi: https://doi.org/10.1101/2021.06.03.446863; this version posted June 5, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. One Sentence Summary: Non-coding genetics demonstrate rare variants in IL-18 receptor 3’UTR that modifies ALS risk and progression. 4 bioRxiv preprint doi: https://doi.org/10.1101/2021.06.03.446863; this version posted June 5, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 [Main Text:] 2 Introduction 3 Genomic sequencing technologies facilitate identification of variants in open reading frames (ORFs). 4 Although allelic variants in non-coding regions are expected to be numerous 1, 2 they are largely 5 overlooked because current analytical approaches do not adequately prioritize variants that are likely to 6 be functional, over neutral background variation. 7 Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative syndrome, primarily affecting the human 8 motor neuron system with a strong genetic predisposing component 3, 4. Thus, mutations in approximately 9 25 protein-coding genes have been associated with ALS 3, 5, 6 and a hexanucleotide repeat expansion in an 10 intronic sequence of the C9orf72 gene is the most common genetic cause of ALS 7-9. However, non-coding 11 nucleotide variants in ALS have yet to be systematically explored. 12 MicroRNAs (miRNAs) are endogenous posttranscriptional repressors that silence mRNA expression 13 through sequence complementarity. miRNA dysregulation has been implicated in ALS pathogenesis, and 14 ALS-associated RNA-binding proteins, TARDBP/TDP-43 and FUS, regulate miRNA biogenesis 10-21. 15 miRNA primarily act on 3′ untranslated regions (3′UTRs) 22, which are non-coding parts of messenger 16 RNAs (mRNAs) and often regulate degradation and translation 23. 17 Burden analysis is a genetics approach that is based on the rationale that different rare variants in the same 18 gene may have a cumulative contribution 24. Therefore, burden analysis allows the identification of genes 19 containing an excess of rare and presumably functional variation in cases relative to controls. Although 20 de novo mutations in non-coding regions were recently shown in family-based autism studies 25, variants 21 in non-coding regions are not routinely included in rare-variant burden association studies. The application 22 of burden analysis to non-coding regulatory variation is constrained by the availability of whole genome 23 sequencing (WGS) data, and the ability to recognize functional variants in non-coding regulatory regions, 24 which is currently far less effective than for protein-coding genes. 25 To effectively apply burden analyses to regulatory variation, appropriate ways to determine what are the 26 relevant (qualifying) variants should be determined. In the case of miRNAs and miRNA recognition 27 elements such a framework can be achieved with relatively high confidence because of miRNA high 5 bioRxiv preprint doi: https://doi.org/10.1101/2021.06.03.446863; this version posted June 5, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 28 conservation and wealth of mechanistic insight about sequence impact on function. Therefore, miRNA 29 regulatory networks make an excellent gene set to explore. 30 Here, we developed tools that identify, or call, qualifying variants in miRNAs and 3′UTR of mRNAs, and 31 performed collapsed genetic analysis 26, to test if these regulatory RNAs are associated with ALS. We 32 discovered an enrichment of rare variants in the IL18RAP 3′UTR, implicating the IL-18 pathway in ALS. 33 Non-coding variants analysis in miRNA networks may impact research of human traits, increase the power 34 of rare-variant association methods and encourage systematic exploration of non-coding regions, to 35 uncover genetic mechanisms of disease. 6 bioRxiv preprint doi: https://doi.org/10.1101/2021.06.03.446863; this version posted June 5, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 36 Results 37 To test whether genetic variations in non-coding regulatory regions are associated with ALS, we analyzed 38 regions of interest WGS data from the Project MinE ALS sequencing consortium
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