Rare variants in MYH15 modify amyotrophic lateral sclerosis risk

• Type of Material: Article
• Authors: Hyerim Kim, Emory University; Junghwa Lim, Emory University; Han Bao, Emory University; Bin Jiao, Emory University; Se Min Canon, Emory University; Michael Epstein, Emory University; Keqin Xu, Emory University; Jie Jiang, Emory University; Janani Parameswaran, Emory University; Yingjie Li, Emory University; Kenneth Moberg, Emory University; John E. Landers, University of Massachusetts; Christina Fournier, Emory University; Emily Allen, Emory University; Jonathan D. Glass, Emory University; Thomas Wingo, Emory University; Peng Jin, Emory University
• Language: English
• Date: 2019-07-15
• Publisher: Oxford University Press
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2019. Published by Oxford University Press. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1093/hmg/ddz063
• Title of Journal or Parent Work: Human Molecular Genetics
• Volume: 28
• Issue: 14
• Start Page: 2309
• End Page: 2318
• Grant/Funding Information: This work was supported in part by the National Institutes of Health (NS051630, NS091859 and NS097206 to P.J.;; NS073873 to J.E.L.;; AG025688), the Veterans Health Administration (BX001820 to T.S.W.) and the American ALS Association (to J.E.L. and J.D.G).; AG056533 to T.S.W.
• Keywords: Stress; Disease; Genetics & Heredity; Expansion; Neurodegeneration; Mutations; C9ORF72; Drosophila; Life Sciences & Biomedicine; General framework; Biochemistry & Molecular Biology; GGGGCC repeat; Science & Technology; Heritability
• Research Categories: Biology, Genetics; Chemistry, Biochemistry; Biology, Neuroscience; Biology, Molecular

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder characterized by progressive muscular atrophy and respiratory failure. The G4C2 repeat expansion in the C9orf72 gene is the most prevalent genetic risk for ALS. Mutation carriers (C9ALS) display variability in phenotypes such as age-at-onset and duration, suggesting the existence of additional genetic factors. Here we introduce a three-step gene discovery strategy to identify genetic factors modifying the risk of both C9ALS and sporadic ALS (sALS) using limited samples. We first identified 135 candidate genetic modifiers of C9ALS using whole-genome sequencing (WGS) of extreme C9ALS cases diagnosed ~30 years apart. We then performed an unbiased genetic screen using a Drosophila model of the G4C2 repeat expansion with the genes identified from WGS analysis. This genetic screen identified the novel genetic interaction between G4C2 repeat-associated toxicity and 18 genetic factors, suggesting their potential association with C9ALS risk. We went on to test if 14 out of the 18 genes, those which were not known to be risk factors for ALS previously, are also associated with ALS risk in sALS cases. Gene-based-statistical analyses of targeted resequencing and WGS were performed. These analyses together reveal that rare variants in MYH15 represent a likely genetic risk factor for ALS. Furthermore, we show that MYH15 could modulate the toxicity of dipeptides produced from expanded G4C2 repeat. Our study presented here demonstrates the power of combining WGS with fly genetics to facilitate the discovery of fundamental genetic components of complex traits with a limited number of samples.