UNIVERSITY OF MASSACHUSETTS

Full Human Genome Sequencing in ALS - 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 pro-posed 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 over-lap 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 path-ways 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 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 diseases. 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.

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