New York Genome Center (NYGC) ALS Consortium at the Center for of Neurodegenerative Disease (CGND)

The CGND at NYGC has formed an ALS consortium with clinicians, scientists, geneticists, computational biologists, and industry partners. The Consortium establishes a framework to apply state-of-the-art clinical and functional genomics together with to the study of ALS disease mechanisms. In partnership with the Genomics Translation for Clinical Partners in the NYGC ALS Care (GTAC) Consortium at , the target is whole genome sequencing and Consortium include 22 institutions: analysis of 3,200 clinically well-annotated ALS samples within the next 3 years, of which we have already sequenced and delivered 1,000. The goal of this focused effort is to discover Academic Medical Center, Amsterdam; ALS Association; how mutations underlying ALS cause disease, thereby contributing valuable information to Cedars-Sinai Medical Center; enhance early diagnosis and effective drug discovery. Columbia University Medical Center; Henry Ford Health Rationale: System; the Jackson Laboratory; • Integrate eQTL, regulatory region, Johns Hopkins University; Advances in the ALS field require Massachusetts General Hospital; overcoming the following challenges: interactome, conservation, and Massachusetts Institute of population-scale data • Limited understanding of known ALS Technology; New York Genome 3. Build functional genomics program: Center; ; Penn genes: minimal genotype-phenotype design, create, and share ALS models to State University; the Rockefeller correlations for ALS genes and a study mutation effects in stem cell University; Simons Foundation; paucity of laboratory models to Target ALS; the Tow Foundation; derived neurons and mice University College London/Queen understand pathomechanisms Mary Institution; University of • Incomplete catalog of causative ALS • Develop tools for large-scale data Maryland Medical genes and driver pathways: known • Study cell-specific RNA-seq and role Center; University of California at of RNA-binding proteins Irvine; University of California, genes currently explain 50% of familial San Francisco; University of ALS and only 10% of sporadic disease • Integrate high-resolution imaging Pennsylvania; and University of • ALS patients are currently stratified by • Share models with community Thessaly, Greece. clinical manifestations rather than 4. Create and maintain a data warehouse The ALS Consortium works in pathomechanisms. This is further for genomic data that can be broadly synergy with other ALSA-funded complicated by: clinical heterogeneity, accessed by and freely available to the consortia, such as the GTAC academic community Consortium headquartered at multiple pathomechanisms, lack of biomarkers, and small datasets unable Columbia. GTAC, directed by Impact of Needed Additional Funds: Matthew Harms, consists of an to drive statistical analyses established network of ALS Additional support to this program will centers already collaborating to Goals: not only advance and accelerate the work recruit subjects for genetic studies. Coordinating the NYGC 1. Integrate genomic and clinical data to outlined above, but will ultimately enable and Columbia efforts makes this identify genetic modifiers of disease us to leverage our synergistic scientific the single largest and best onset, progression, and presentation and institutional resources to create a characterized ALS study to date. • Sequence well-stratified cohorts world-class center of excellence for Pre-Competitive Data Sharing: • Harmonize early and longitudinal genomics research in ALS. • Immediate post QC release of clinical phenotyping across centers • Empower clinical informatics of the de-identified clinical and • Target relevant individuals for NYGC ALS Consortium samples to genetic data to all consortium additional studies: imaging and members (including for-profit enable joint analysis with GTAC partners contributing towards specimen collection • Advance biospecimen collections in data collection and sequencing) 2. Combine whole genome sequencing select populations • Data is collected to allow for with RNA sequencing • Enable analysis of RNA-seq data from broad sharing; sharing with autopsy tissue other parties (“general • Profile fresh-frozen samples from research community”) to be different regions of the motor system • Develop functional genomics program gated by a Data Access • Interrogate relationship between • Propel data warehousing Committee constituted of sequence variation and expression infrastructure, management, sharing, consortium members • Focus on both risk and disease- and integration • Data to be deposited in dbGaP and/or similar repositories regulation mutations

concomitant with the earlier of The New York Genome Center (NYGC) is an independent non-profit implementing advanced genomic research manuscript submission/ to improve diagnosis and treatment of serious diseases. The NYGC ALS Consortium is led by Hemali Phatnani, publication or 6 months after who directs the CGND at NYGC and is Adjunct Assistant Professor of Neurological Sciences at CUMC in the completion of primary studies Department of Neurology and the Institute for Genomic Medicine. David Goldstein (Director of the Institute for NEW YORK GENOME CENTER Genomic Medicine and Professor of Genetics and Development in the College of Physicians and Surgeons at 101 Avenue of the Americas, 7th Floor CUMC), Tom Maniatis (Isidore S. Edelman Professor of Biochemistry, Chair of the Department of Biochemistry New York, NY 10013 and Molecular Biophysics, and Director of Precision Medicine at CUMC), Richard Mayeux (Chair & Neurologist- www.nygenome.org in-Chief, Department of Neurology and Co-director, Taub Institute for Research on Alzheimer's Disease and the Email: [email protected] Aging Brain at CUMC), and Cheryl A. Moore (President and COO of NYGC) are advisors to the CGND. NYGC-CUMC INTEGRATED ALS PROGRAM – MILESTONES AND DELIVERABLES

2015 2016 2017 2018 ADMINISTRATIVE INFRASTRUCTURE MTAs, ICFs, IRB Protocols, Consortium 23 sites and growing Agreements, Partnerships

BIOSPECIMENS 600 1400 3200 DNA 200 800 1500 PBMCs RNA (Blood) 200 800 1500 Autopsy Tissue 60 120 180 RNA (Tissue) 360 720 1080

LONGITUDINAL BIOSPECIMENS 1000 2000 3000 Plasma 1000 2000 3000 PLANNED IN PARTNERSHIP Serum WITH TARGET ALS CSF TBD TBD TBD CLINICAL INFORMATICS AND SEQUENCING 600 1400 3200 WGS RNASeq 560 1520 2580 Clinical Data (Cross-sectional and 600 1400 3200 Progressive) Burden analysis used Curate entire catalog of Expand curated ALS Develop standards for DATA ANALYSIS AND for the first time to reported ALS mutations gene resource based on the clinical diagnostic identify new ALS genes based on levels of genetic additional genotypes interpretation of ALS INTERPRETATION (TBK1 and OPTN) and functional evidence from sequencing genomes

FUNCTIONAL GENOMICS FUS, TBK1, OPTN, + +3 TBD +4 TBD Total of 10 new models Mouse Models combinatorial models • Prioritization of mutations for model building based on human data and predictions • WGS interpretation will be combined with pathogenicity models developed at the IGM and based on intolerance scores, to select specific variants for modeling