Amyotrophic lateral sclerosis (ALS) is a progressively fatal neurodegenerative disease affecting motor neurons in the brain and spinal cord. In this study, we investigated gene expression changes in ALS via RNA sequencing in 380 postmortem samples from cervical, thoracic and lumbar spinal cord segments from 154 individuals with ALS and 49 control individuals. We observed an increase in microglia and astrocyte gene expression, accompanied by a decrease in oligodendrocyte gene expression. By creating a gene co-expression network in the ALS samples, we identified several activated microglia modules that negatively correlate with retrospective disease duration. We mapped molecular quantitative trait loci and found several potential ALS risk loci that may act through gene expression or splicing in the spinal cord and assign putative cell types for FNBP1, ACSL5, SH3RF1 and NFASC. Finally, we outline how common genetic variants associated with splicing of C9orf72 act as proxies for the well-known repeat expansion, and we use the same mechanism to suggest ATXN3 as a putative risk gene.
Jack Humphrey 1 2 3 4, Sanan Venkatesh 5 6 7, Rahat Hasan 5 8 6 9, Jake T Herb 10, Katia de Paiva Lopes 5 8 6 9, Fahri Küçükali 11 12, Marta Byrska-Bishop 13, Uday S Evani 13, Giuseppe Narzisi 13, Delphine Fagegaltier 13 14; NYGC ALS Consortium; Kristel Sleegers 11 12, Hemali Phatnani 13 14 15, David A Knowles 13 16, Pietro Fratta 17, Towfique Raj 18 19 20 21
1 Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
2 Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
3 Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
4 Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
5 Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
6 Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
7 Department of Psychiatry, Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
8 Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
9 Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
10 Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
11 Complex Genetics of Alzheimer’s Disease Group, Center for Molecular Neurology, VIB, Antwerp, Belgium.
12 Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
13 New York Genome Center, New York, NY, USA.
14 Center for Genomics of Neurodegenerative Disease, New York Genome Center, New York, NY, USA.
15 Department of Neurology, Columbia University Irving Medical Center, Columbia University, New York, NY, USA.
16 Department of Computer Science, Columbia University, New York, NY, USA.
17 Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK.
18 Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
19 Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
20 Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
21 Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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