Year: 2012
Type: article
Study design: Observational Study
Abstract: Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disease characterized by loss of upper and lower motor neurons. ALS is considered to be a complex trait and genome-wide association studies (GWAS) have implicated a few susceptibility loci. However, many more causal loci remain to be discovered. Since it has been shown that genetic variants associated with complex traits are more likely to be eQTLs than frequency-matched variants from GWAS platforms, we conducted a two-stage genome-wide screening for eQTLs associated with ALS. In addition, we applied an eQTL analysis to finemap association loci. Expression profiles using peripheral blood of 323 sporadic ALS patients and 413 controls were mapped to genome-wide genotyping data. Subsequently, data from a two-stage GWAS (3,568 patients and 10,163 controls) were used to prioritize eQTLs identified in the first stage (162 ALS, 207 controls). These prioritized eQTLs were carried forward to the second sample with both gene-expression and genotyping data (161 ALS, 206 controls). Replicated eQTL SNPs were then tested for association in the second-stage GWAS data to find SNPs associated with disease, that survived correction for multiple testing. We thus identified twelve cis eQTLs with nominally significant associations in the second-stage GWAS data. Eight SNP-transcript pairs of highest significance (lowest p = 1.27 × 10(-51)) withstood multiple-testing correction in the second stage and modulated CYP27A1 gene expression. Additionally, we show that C9orf72 appears to be the only gene in the 9p21.2 locus that is regulated in cis, showing the potential of this approach in identifying causative genes in association loci in ALS. This study has identified candidate genes for sporadic ALS, most notably CYP27A1. Mutations in CYP27A1 are causal to cerebrotendinous xanthomatosis which can present as a clinical mimic of ALS with progressive upper motor neuron loss, making it a plausible susceptibility gene for ALS.
Source: PLoS ONE
Authors: Frank P. Diekstra, Christiaan G. J. Saris, Wouter van Rheenen, Lude Franke, Ritsert C. Jansen, Michael A. van Es, Paul W. J. van Vught, Hylke M. Blauw, Ewout J. N. Groen, Steve Horvath, Karol Estrada, Fernando Rivadeneira, Albert Hofman, Andre G. Uitterlinden, Wim Robberecht, Peter M. Andersen, Judith Melki, Vincent Meininger, Orla Hardiman, John E. Landers, Robert H. Brown, Aleksey Shatunov, Christopher E. Shaw, P. Nigel Leigh, Ammar Al-Chalabi, Roel A. Ophoff, Leonard H. van den Berg, Jan H. Veldink
Institutions: University Medical Center Utrecht, University Medical Center Groningen, University of Groningen, University of California, Los Angeles, Erasmus MC, Erasmus University Rotterdam, Vlaams Instituut voor Biotechnologie, KU Leuven, Umeå University, Université Paris Cité, Bicêtre Hospital, Pitié-Salpêtrière Hospital, Université Pierre-et-Marie-Curie, Trinity College Dublin, Beaumont Hospital, University of Massachusetts Chan Medical School, Massachusetts General Hospital, King's College London, Medical Research Council, Utrecht University
Language: Dutch
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,382
Funders: Brain Research Foundation, Muscular Dystrophy Association, ALS Therapy Alliance, Wellcome Trust, Health Research Board, Psychiatry Research Trust, Motor Neurone Disease Association, European Commission, ZonMw, Belgian Federal Science Policy Office, Erasmus Medisch Centrum, Ministerie van Onderwijs, Cultuur en Wetenschap, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, VSB Fonds, Adessium Foundation, Svenska Läkaresällskapet, National Institutes of Health, U.S. Public Health Service, Medical Research Council, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke
Awards: G1093531541, G119964413, G1332191200, G1495020029, G189631895, G2079419724, G2852867444, G2861369480, G2973790809, G300339986, G3207356259, G3540777072, G3839646794, G3864425901, G393177772, G4842425482, G494123624, RNA processing proteins and neurodegeneration: exploring mechanisms and modelling disease., G5123667768, G5457026379, G5702163051, G5724314488, G601508740, G6320440117, G7159839810, G8506930532, G864096937, European multidisciplinary ALS network identification to cure motor neuron degeneration, G890705022, G8927421343, G9000097764, G9000103269, Cancer Center Support Grant, G955553568
OpenAlex ID: W2143143063