1. Genome-wide identification of the genetic basis of amyotrophic lateral sclerosis
- Author
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Sai Zhang, Johnathan Cooper-Knock, Annika K. Weimer, Minyi Shi, Tobias Moll, Jack N.G. Marshall, Calum Harvey, Helia Ghahremani Nezhad, John Franklin, Cleide dos Santos Souza, Ke Ning, Cheng Wang, Jingjing Li, Allison A. Dilliott, Sali Farhan, Eran Elhaik, Iris Pasniceanu, Matthew R. Livesey, Chen Eitan, Eran Hornstein, Kevin P. Kenna, Jan H. Veldink, Laura Ferraiuolo, Pamela J. Shaw, Michael P. Snyder, Ian Blair, Naomi R. Wray, Matthew Kiernan, Miguel Mitne Neto, Adriano Chio, Ruben Cauchi, Wim Robberecht, Philip van Damme, Philippe Corcia, Philippe Couratier, Orla Hardiman, Russell McLaughin, Marc Gotkine, Vivian Drory, Nicola Ticozzi, Vincenzo Silani, Leonard H. van den Berg, Mamede de Carvalho, Jesus S. Mora Pardina, Monica Povedano, Peter Andersen, Markus Weber, Nazli A. Başak, Ammar Al-Chalabi, Chris Shaw, Karen E. Morrison, John E. Landers, Jonathan D. Glass, and Project MinE ALS Sequencing Consortium more...
- Subjects
Motor Neurons ,Cell Death ,General Neuroscience ,Amyotrophic Lateral Sclerosis ,Induced Pluripotent Stem Cells ,Cytoskeletal Proteins ,Amyotrophic lateral sclerosis -- Diagnosis ,Genes ,Machine learning ,Genetics ,Humans ,Epigenetics ,Nervous system -- Degeneration ,Adaptor Proteins, Signal Transducing ,Genome-Wide Association Study - Abstract
Amyotrophic lateral sclerosis (ALS) is a complex disease that leads to motor neuron death. Despite heritability estimates of 52%, genome-wide association studies (GWASs) have discovered relatively few loci. We developed a machine learning approach called RefMap, which integrates functional genomics with GWAS summary statistics for gene discovery. With transcriptomic and epigenetic profiling of motor neurons derived from induced pluripotent stem cells (iPSCs), RefMap identified 690 ALS-associated genes that represent a 5-fold increase in recovered heritability. Extensive conservation, transcriptome, network, and rare variant analyses demonstrated the functional significance of candidate genes in healthy and diseased motor neurons and brain tissues. Genetic convergence between common and rare variation highlighted KANK1 as a new ALS gene. Reproducing KANK1 patient mutations in human neurons led to neurotoxicity and demonstrated that TDP-43 mislocalization, a hallmark pathology of ALS, is downstream of axonal dysfunction. RefMap can be readily applied to other complex diseases., peer-reviewed more...
- Published
- 2021