Journal article

A new approach for rare variation collapsing on functional protein domains implicates specific genic regions in ALS

Sahar Gelfman, Sarah Dugger, Cristiane de Araujo Martins Moreno, Zhong Ren, Charles J Wolock, Neil A Shneider, Hemali Phatnani, Elizabeth T Cirulli, Brittany N Lasseigne, Tim Harris, Tom Maniatis, Guy A Rouleau, Robert H Brown, Aaron D Gitler, Richard M Myers, Slave Petrovski, Andrew Allen, David B Goldstein, Matthew B Harms

GENOME RESEARCH | COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT | Published : 2019

Abstract

Large-scale sequencing efforts in amyotrophic lateral sclerosis (ALS) have implicated novel genes using gene-based collapsing methods. However, pathogenic mutations may be concentrated in specific genic regions. To address this, we developed two collapsing strategies: One focuses rare variation collapsing on homology-based protein domains as the unit for collapsing, and the other is a gene-level approach that, unlike standard methods, leverages existing evidence of purifying selection against missense variation on said domains. The application of these two collapsing methods to 3093 ALS cases and 8186 controls of European ancestry, and also 3239 cases and 11,808 controls of diversified popul..

View full abstract

University of Melbourne Researchers

Grants

Awarded by ALS Association


Awarded by Bryan ADRC NIA


Awarded by NIH


Awarded by National Institute of Allergy and Infectious Diseases Center for HIV/AIDS Vaccine Immunology (CHAVI)


Awarded by NINDS Award


Awarded by Epi4K Gene Discovery in Epilepsy study


Awarded by Epilepsy Genome/Phenome Project


Awarded by Ellison Medical Foundation New Scholar award


Awarded by B57 SAIC-Fredrick Inc.


Awarded by NIMH


Awarded by NIH Clinical and Translational Science Award Program


Awarded by Washington Heights-Inwood Columbia Aging Project (WHICAP) - National Institute on Aging (NIA)


Awarded by National Center for Advancing Translational Sciences, National Institutes of Health


Awarded by Clinical and Translational Science Awards TL1 Training Award


Awarded by R.D. Wright Career Development Fellowship (National Health and Medical Research Council)


Awarded by Murdock Study Community Registry and Biorepository


Awarded by National Institute on Aging



Awarded by EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT


Awarded by NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES


Awarded by NATIONAL HUMAN GENOME RESEARCH INSTITUTE


Awarded by NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES


Awarded by NATIONAL INSTITUTE OF MENTAL HEALTH


Awarded by NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE


Awarded by NATIONAL INSTITUTE ON AGING


Funding Acknowledgements

The collection and sequencing of ALS cases for the New York Genome Center ALS Consortium was funded by the ALS Association and the Tow Foundation. Collection of samples, and sequencing for the GTAC study was funded by a partnership of the ALS Association and Biogen Idec. Sequencing of cases for the ALS Sequencing Consortium was funded by Biogen Idec.We thank The Washington Heights-Inwood Columbia Aging Project (WHICAP) for the contribution of control samples. We also thank the WHICAP study participants and the WHICAP research and support staff for their contributions to this study: S. Kerns and H. Oster; K. Welsh-Bomer, C. Hulette, and J. Burke; F. McMahon and N. Akula; D. Valle, J. Hoover-Fong, and N. Sobriera; A. Poduri; S. Palmer; R. Buckley; and N. Calakos; The Murdock Study Community Registry and Biorepository Pro00011196; National Institute of Allergy and Infectious Diseases Center for HIV/AIDS Vaccine Immunology (CHAVI) (U19-AI067854); CHAVI Funding; R. Ottman; V. Shashi; E. Holtzman; S. Berkovic, I. Scheffer, and B. Grinton; The Epi4K Consortium and Epilepsy Phenome/Genome Project; C. Depondt, S. Sisodiya, G. Cavalleri, and N. Delanty; The ALS Sequencing Consortium (see above); The Washington University Neuromuscular Genetics Project; C. Woods, C. Village, K. Schmader, S. McDonald, M. Yanamadala, and H. White; G. Nestadt, J. Samuels, and Y. Wang; S. Schuman and E. Nading; D. Marchuk; D. Levy; E. Pras, D. Lancet, and Z. Farfel; Y. Jiang; T. Young and K. Whisenhunt; J. Milner; C. Moylan, A. Mae Diehl, and M. Abdelmalek; DUHS (Duke University Health System) Nonalcoholic Fatty Liver Disease Research Database and Specimen Repository; M. Winn and R. Gbadegesin; M. Hauser; S. Delaney; A. Need and J. McEvoy; A. Holden and E. Behr; M. Walker; M. Sum; Undiagnosed Diseases Network; National Institute on Aging (R01AG037212, P01AG007232).The collection of control samples and data was funded in part by: Bryan ADRC NIA P30 AG028377; NIH RO1 HD048805; Gilead Sciences, Inc.; D. Murdock; National Institute of Allergy and Infectious Diseases Center for HIV/AIDS Vaccine Immunology (CHAVI) (U19-AI067854); Bill and Melinda Gates Foundation; NINDS Award# RC2NS070344; New York-Presbyterian Hospital; The Columbia University College of Physicians and Surgeons; The Columbia University Medical Center; NIH U54 NS078059; NIH P01 HD080642; The J. Willard and Alice S. Marriott Foundation; The Muscular Dystrophy Association; The Nicholas Nunno Foundation; The JDM Fund for Mitochondrial Research; The Arturo Estopinan TK2 Research Fund; UCB; Epi4K Gene Discovery in Epilepsy study (NINDS U01-NS077303) and The Epilepsy Genome/Phenome Project (EPGP - NINDS U01-NS053998); Biogen; The Ellison Medical Foundation New Scholar award AG-NS-0441-08; B57 SAIC-Fredrick Inc. M11-074; 1R01MH097971-01A1. This research was supported in part by funding from The Division of Intramural Research, NIAID, NIH; Funding from the Duke Chancellor's Discovery Program Research Fund 2014; an American Academy of Child and Adolescent Psychiatry (AACAP) Pilot Research Award; NIMH Grant RC2MH089915; Endocrine Fellows Foundation Grant; The NIH Clinical and Translational Science Award Program (UL1TR000040); NIH U01HG007672; The Washington Heights Inwood Columbia Aging Project; and The Stanley Institute for Cognitive Genomics at Cold Spring Harbor Laboratory. Data collection and sharing for the WHICAP project (used as controls in this analysis) was supported by The Washington Heights-Inwood Columbia Aging Project (WHICAP, PO1AG07232, R01AG037212, RF1AG054023) funded by the National Institute on Aging (NIA) and by The National Center for Advancing Translational Sciences, National Institutes of Health, through Grant Number UL1TR001873. This manuscript has been reviewed by WHICAP investigators for scientific content and consistency of data interpretation with previous WHICAP Study publications. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.S.D. was funded by the Clinical and Translational Science Awards TL1 Training Award (5TL1TR001875-03); S.P. was funded by R.D. Wright Career Development Fellowship (National Health and Medical Research Council, 1126877); M.B.H. was funded by the Eleanor and Lou Gehrig ALS Center at Columbia University research fund, the ALS Association, Greater New York Chapter of the ALS Association, and Biogen Idec. Work in the Center for Genomics of Neurodegenerative Disease is supported by The ALS Association (grant number 15-LGCA-234) and The Tow Foundation.