Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology.

Nature Genetics
Wouter van RheenenJan H Veldink

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.

References

Jul 24, 2001·Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders : Official Publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases·B R BrooksUNKNOWN World Federation of Neurology Research Group on Motor Neuron Diseases
May 22, 2008·Proceedings of the National Academy of Sciences of the United States of America·Koji YamanakaLawrence S B Goldstein
Apr 3, 2009·Nature·Rajat SinghMark J Czaja
Jul 16, 2009·Genome Research·Sung Chun, Justin C Fay
Apr 1, 2010·Nature Methods·Ivan A AdzhubeiShamil R Sunyaev
May 4, 2010·Nature Biotechnology·Cory Y McLeanGill Bejerano
Jul 10, 2010·Bioinformatics·Cristen J WillerGonçalo R Abecasis
Jul 22, 2010·Autophagy·Hiroshi KogaAna Maria Cuervo
Aug 31, 2010·Lancet Neurology·Hannu LaaksovirtaBryan J Traynor
Dec 21, 2010·American Journal of Human Genetics·Jian YangPeter M Visscher
Jul 6, 2011·Nucleic Acids Research·Boris RevaChris Sander
Nov 11, 2011·Journal of Neurology, Neurosurgery, and Psychiatry·Martin R TurnerMichael J Goldacre
Mar 9, 2012·Journal of Neurology, Neurosurgery, and Psychiatry·Susan ByrneOrla Hardiman
May 16, 2013·Acta Neuropathologica·Anna M BlokhuisR Jeroen Pasterkamp
Oct 8, 2013·Nature Genetics·Cristen J WillerUNKNOWN Global Lipids Genetics Consortium
Mar 25, 2014·American Journal of Human Genetics·Daniel WooUNKNOWN International Stroke Genetics Consortium
Apr 1, 2014·Nature Methods·Jana Marie SchwarzDominik Seelow
Jun 20, 2014·Lancet Neurology·Raffaele FerrariParastoo Momeni
Jul 25, 2014·Nature·UNKNOWN Schizophrenia Working Group of the Psychiatric Genomics Consortium
Jul 26, 2014·Journal of Neurology·Meinie SeelenLeonard H van den Berg
Jul 30, 2014·Human Molecular Genetics·George Davey Smith, Gibran Hemani
Jan 30, 2015·American Journal of Epidemiology·Stephen Burgess, Simon G Thompson
Feb 3, 2015·Nature Genetics·Brendan K Bulik-SullivanBenjamin M Neale
Feb 24, 2015·Science·Elizabeth T CirulliDavid B Goldstein
Mar 25, 2015·Nature Neuroscience·Axel FreischmidtJochen H Weishaupt
Apr 18, 2015·PLoS Computational Biology·Christiaan A de LeeuwDanielle Posthuma
Jun 11, 2015·Proceedings of the National Academy of Sciences of the United States of America·Spyros DarmanisStephen R Quake
Aug 21, 2015·Acta Biochimica Et Biophysica Sinica·Xiao FangPumin Zhang
Dec 4, 2015·Nature Protocols·Robert VaserPauline C Ng
Jan 13, 2016·Molecular Psychiatry·T OtowaJ M Hettema
Jan 26, 2016·PLoS Computational Biology·David LamparterSven Bergmann
Feb 9, 2016·Nature Genetics·Alexander GusevBogdan Pasaniuc
Mar 8, 2016·Brain : a Journal of Neurology·David BrennerJochen H Weishaupt
Jun 21, 2016·American Journal of Human Genetics·Brielin C BrownNoah Zaitlen

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Citations

Dec 8, 2021·Nature Genetics·Sunil Sahdeo, David B Goldstein

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