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Genome-wide identification of the genetic basis of amyotrophic lateral sclerosis

Zhang, Sai ; Cooper-Knock, Johnathan ; Weimer, Annika K ; Shi, Minyi ; Moll, Tobias ; Marshall, Jack N G ; Harvey, Calum ; Nezhad, Helia Ghahremani ; Franklin, John and Souza, Cleide Dos Santos , et al. (2022) In Neuron 110(6). p.11-1008
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... (More)

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.

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author collaboration
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Neuron
volume
110
issue
6
pages
11 - 1008
publisher
Cell Press
external identifiers
  • pmid:35045337
  • scopus:85126111540
ISSN
0896-6273
DOI
10.1016/j.neuron.2021.12.019
language
English
LU publication?
yes
additional info
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
id
fa7bcf82-1b6e-47b3-b8d8-c1e2e0ec77e4
date added to LUP
2022-02-21 15:35:50
date last changed
2024-06-28 15:14:19
@article{fa7bcf82-1b6e-47b3-b8d8-c1e2e0ec77e4,
  abstract     = {{<p>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.</p>}},
  author       = {{Zhang, Sai and Cooper-Knock, Johnathan and Weimer, Annika K and Shi, Minyi and Moll, Tobias and Marshall, Jack N G and Harvey, Calum and Nezhad, Helia Ghahremani and Franklin, John and Souza, Cleide Dos Santos and Ning, Ke and Wang, Cheng and Li, Jingjing and Dilliott, Allison A and Farhan, Sali and Elhaik, Eran and Pasniceanu, Iris and Livesey, Matthew R and Eitan, Chen and Hornstein, Eran and Kenna, Kevin P and Veldink, Jan H and Ferraiuolo, Laura and Shaw, Pamela J and Snyder, Michael P}},
  issn         = {{0896-6273}},
  language     = {{eng}},
  month        = {{01}},
  number       = {{6}},
  pages        = {{11--1008}},
  publisher    = {{Cell Press}},
  series       = {{Neuron}},
  title        = {{Genome-wide identification of the genetic basis of amyotrophic lateral sclerosis}},
  url          = {{http://dx.doi.org/10.1016/j.neuron.2021.12.019}},
  doi          = {{10.1016/j.neuron.2021.12.019}},
  volume       = {{110}},
  year         = {{2022}},
}