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Genome-Wide Identification of the Genetic Basis of Amyotrophic Lateral Sclerosis

71 Pages Posted: 7 Dec 2020 Publication Status: Review Complete

See all articles by Sai Zhang

Sai Zhang

Stanford University - Stanford Center for Genomics and Personalized Medicine

Johnathan Cooper-Knock

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

Annika K. Weimer

Stanford University - Department of Genetics

Minyi Shi

Stanford University - Department of Genetics

Tobias Moll

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

Calum Harvey

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

Helia Ghahremani Nezhad

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

John Franklin

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

Cleide dos Santos Souza

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

Cheng Wang

University of California, San Francisco (UCSF) - Department of Neurology

Jingjing Li

University of California, San Francisco (UCSF) - Department of Neurology

Chen Eitan

Weizmann Institute of Science - Department of Molecular Genetics

Eran Hornstein

Weizmann Institute of Science - Department of Molecular Genetics

Kevin P. Kenna

University Medical Center Utrecht - Department of Neurology

Project MinE Sequencing Consortium

Independent

Jan H. Veldink

Utrecht University - Department of Neurology

Laura Ferraiuolo

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

Pamela J. Shaw

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

Michael P. Snyder

Stanford University - Stanford Center for Genomics and Personalized Medicine

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Abstract

Amyotrophic lateral sclerosis (ALS) is a complex disease centered on progressive death of motor neurons. Despite heritability estimates of 52%, GWAS studies have discovered only seven genome-wide significant hits. We developed a new machine learning approach called RefMap that integrates functional genomics with ALS genetics. Comprehensive transcriptomic and epigenetic profiling of iPSC-derived motor neurons enabled RefMap to identify 690 genes associated with ALS, the majority of which are novel. Extensive conservation, transcriptome and network analyses demonstrated the functional significance of these candidate genes in motor neurons and disease progression, and our genetic results support initiation of ALS neurotoxicity in the distal axon. KANK1 is enriched with coding and noncoding, common and rare ALS-associated variants. Reproducing patient KANK1 mutations in human neurons led to neurotoxicity with disruption of the distal axon. RefMap can be applied broadly to increase the discovery power in genetic association studies of human complex traits and diseases.

Suggested Citation

Zhang, Sai and Cooper-Knock, Johnathan and Weimer, Annika K. and Shi, Minyi and Moll, Tobias and Harvey, Calum and Nezhad, Helia Ghahremani and Franklin, John and Souza, Cleide dos Santos and Wang, Cheng and Li, Jingjing and Eitan, Chen and Hornstein, Eran and Kenna, Kevin P. and Consortium, Project MinE Sequencing and Veldink, Jan H. and Ferraiuolo, Laura and Shaw, Pamela J. and Snyder, Michael P., Genome-Wide Identification of the Genetic Basis of Amyotrophic Lateral Sclerosis. Available at SSRN: https://ssrn.com/abstract=3744427 or http://dx.doi.org/10.2139/ssrn.3744427
This version of the paper has not been formally peer reviewed.

Sai Zhang

Stanford University - Stanford Center for Genomics and Personalized Medicine

Stanford, CA 94305
United States

Johnathan Cooper-Knock

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN) ( email )

385a Glossop Road
Sheffield
United Kingdom

Annika K. Weimer

Stanford University - Department of Genetics

Stanford, CA 94305
United States

Minyi Shi

Stanford University - Department of Genetics

Stanford, CA 94305
United States

Tobias Moll

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN) ( email )

385a Glossop Road
Sheffield
United Kingdom

Calum Harvey

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

17 Mappin Street
Sheffield, S1 4DT
United Kingdom

Helia Ghahremani Nezhad

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN) ( email )

385a Glossop Road
Sheffield
United Kingdom

John Franklin

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

385a Glossop Road
Sheffield
United Kingdom

Cleide dos Santos Souza

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

17 Mappin Street
Sheffield, S1 4DT
United Kingdom

Cheng Wang

University of California, San Francisco (UCSF) - Department of Neurology

San Francisco, CA 94143
United States

Jingjing Li

University of California, San Francisco (UCSF) - Department of Neurology

San Francisco, CA 94143
United States

Chen Eitan

Weizmann Institute of Science - Department of Molecular Genetics ( email )

Rehovot, 7610001
Israel

Eran Hornstein

Weizmann Institute of Science - Department of Molecular Genetics

Rehovot, 7610001
Israel

Kevin P. Kenna

University Medical Center Utrecht - Department of Neurology ( email )

Utrecht
Netherlands

Jan H. Veldink

Utrecht University - Department of Neurology ( email )

Utrecht
Netherlands

Laura Ferraiuolo

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

17 Mappin Street
Sheffield, S1 4DT
United Kingdom

Pamela J. Shaw

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

17 Mappin Street
Sheffield, S1 4DT
United Kingdom

Michael P. Snyder (Contact Author)

Stanford University - Stanford Center for Genomics and Personalized Medicine

Stanford, CA 94305
United States

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