The causes of most neurodegenerative disorders (ALS, Alzheimer and Parkinson disease) are poorly understood, despite remarkable advances in delineating the molecular pathology in the rare forms of these diseases that are transmitted as Mendelian traits. The proposed project will develop a platform for full genome sequencing that will identify rare genetic variants that underlie both sporadic and familial forms of these disorders their pathogenesis. This project focuses on ALS because of the dire nature of this disease and because it is likely that neural death mechanisms overlap in diverse neurodegenerative disorders;insights into the pathogenesis in ALS will facilitate research in the others. The central hypothesis of this proposal is that the identification of naturally occurring gene variants that predispose to ALS or that modify the phenotype of this disease will identify pathogenic pathways that are targets for the development of new therapeutic strategies. This proposal is a joint effort of two laboratories with complementary and synergistic expertise in ALS and human genetics. The laboratory of Dr. Robert Brown (PI, Neurology, University of Massachusetts Medical School) has a longstanding expertise in the genetics of ALS. With collaborators, it reported the first ALS gene (SOD1) in 1993 and subsequently participated in reports of additional ALS genes including alsin, VAPB, and most recently FIG4, ELP3 and FUS. This group led the multinational genome analysis that identified variants in KIFAP3 as modifiers of survival in ALS. The laboratory of Dr. David Goldstein (Co-PI, Director, The Institute for Genome Science and Policy, Duke University) is among the foremost academic facilities conducting whole-genome sequencing on a significant scale. The laboratory has a proven track record of performing large-scale human genetics studies, and has developed a bioinformatics and biostatistical pipeline for the analysis of the large amounts of data arising from whole-genome sequencing. In our view, this is a timely, cutting edge collaboration that has the potential to be a paradigm shift in studies of the biology of ALS and other neurodegenerative. The project has five specific aims: (1) perform full sequencing of the genome and identification of the genetic variants in 40 ALS cases (20 sporadic, 20 familial);(2) validate the identified variants and prioritize them for further study;(3) genotype the ranked variants in cohorts of 1,000 cases and 1,000 controls and perform association and regression analyses to assess these variants as determinants of susceptibility and/or phenotype;(4) undertake follow-up studies of the functional significance of the significant variants;(5) release the full sequencing data for public use.

Public Health Relevance

Amyotrophic lateral sclerosis, also called ALS or Lou Gehrig's disease, is a lethal degenerative disease of motor nerves that causes weakness and death, usually in less than five years. Several studies suggest that genetic factors are important in this disease, both for the 10% of cases in which ALS runs in families and for the other 90%, in which subtle gene variations are contribute to the process of motor nerve death. We propose to completely determine the sequences of all of the molecules of DNA in a each of 40 individuals with ALS. The findings in these 40 cases will then be further tested in DNA from 1,000 individuals with ALS cases and another 1,000 individuals who do not have ALS. The discovery of gene variants that cause ALS, or that affect the way it evolves, will provide new insight into this devastating disease and, at the same time, identify novel targets for the development of new therapies. This work will be undertaken jointly by a world-class human genetics laboratory directed by Dr. David Goldstein at Duke University and by a laboratory with longstanding experience in ALS genetics at the University of Massachusetts. This is a timely, cutting edge project that has the potential to be a paradigm shift in studies of the biology of ALS;we anticipate that findings from this study will provide insight into other neurodegenerative disorders such as Alzheimer's and Parkinson's diseases.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
High Impact Research and Research Infrastructure Programs (RC2)
Project #
Application #
Study Section
Special Emphasis Panel (ZHG1-HGR-P (O1))
Program Officer
Sutherland, Margaret L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Massachusetts Medical School Worcester
Schools of Medicine
United States
Zip Code
Rittiner, Joseph E; Caffall, Zachary F; Hernández-Martinez, Ricardo et al. (2016) Functional Genomic Analyses of Mendelian and Sporadic Disease Identify Impaired eIF2? Signaling as a Generalizable Mechanism for Dystonia. Neuron 92:1238-1251
Williams, Kelly L; Topp, Simon; Yang, Shu et al. (2016) CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia. Nat Commun 7:11253
Kubat Öktem, Elif; Mruk, Karen; Chang, Joshua et al. (2016) Mutant SOD1 protein increases Nav1.3 channel excitability. J Biol Phys 42:351-70
Fogh, Isabella; Lin, Kuang; Tiloca, Cinzia et al. (2016) Association of a Locus in the CAMTA1 Gene With Survival in Patients With Sporadic Amyotrophic Lateral Sclerosis. JAMA Neurol 73:812-20
Mccarthy, Janice M; Shea, Patrick R; Goldstein, David B et al. (2015) Testing for risk and protective trends in genetic analyses of HIV acquisition. Biostatistics 16:268-80
Peters, Owen M; Ghasemi, Mehdi; Brown Jr, Robert H (2015) Emerging mechanisms of molecular pathology in ALS. J Clin Invest 125:1767-79
Petrovski, Slavé; Gussow, Ayal B; Wang, Quanli et al. (2015) The Intolerance of Regulatory Sequence to Genetic Variation Predicts Gene Dosage Sensitivity. PLoS Genet 11:e1005492
Hall, Gentzon; Gbadegesin, Rasheed A; Lavin, Peter et al. (2015) A novel missense mutation of Wilms' Tumor 1 causes autosomal dominant FSGS. J Am Soc Nephrol 26:831-43
Seijffers, Rhona; Zhang, Jiangwen; Matthews, Jonathan C et al. (2014) ATF3 expression improves motor function in the ALS mouse model by promoting motor neuron survival and retaining muscle innervation. Proc Natl Acad Sci U S A 111:1622-7
Wang, Hongyan; Yang, Bin; Qiu, Linghua et al. (2014) Widespread spinal cord transduction by intrathecal injection of rAAV delivers efficacious RNAi therapy for amyotrophic lateral sclerosis. Hum Mol Genet 23:668-81

Showing the most recent 10 out of 37 publications