1. Mapping of Gene Expression Reveals CYP27A1 as a Susceptibility Gene for Sporadic ALS
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Orla Hardiman, Albert Hofman, Wouter van Rheenen, Michael A. van Es, Ritsert C. Jansen, Frank P. Diekstra, Christopher Shaw, John Landers, Karol Estrada, Wim Robberecht, Steve Horvath, Ammar Al-Chalabi, Vincent Meininger, Hylke M. Blauw, Fernando Rivadeneira, Judith Melki, André G. Uitterlinden, P. Nigel Leigh, Robert H. Brown, Leonard H. van den Berg, Roel A. Ophoff, Aleksey Shatunov, Christiaan G J Saris, Peter M. Andersen, Ewout J N Groen, Jan H. Veldink, Lude Franke, Paul W.J. van Vught, Internal Medicine, Epidemiology, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Bioinformatics, Stem Cell Aging Leukemia and Lymphoma (SALL), and van der Brug, Marcel P
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Candidate gene ,Linkage disequilibrium ,Neurologi ,Gene Expression ,lcsh:Medicine ,Genome-wide association study ,Neurodegenerative ,VARIANTS ,AMYOTROPHIC-LATERAL-SCLEROSIS ,Linkage Disequilibrium ,Motor Neuron Diseases ,0302 clinical medicine ,2.1 Biological and endogenous factors ,TOOL ,Aetiology ,Cytochrome P-450 CYP27A1 ,lcsh:Science ,RISK ,Motor Neurons ,Genetics ,0303 health sciences ,Multidisciplinary ,Neurodegenerative Diseases ,Xanthomatosis, Cerebrotendinous ,Genomics ,Single Nucleotide ,CROHNS-DISEASE ,Pedigree ,Neurology ,RC0346 ,Neurological ,Medicine ,Cholestanetriol 26-Monooxygenase ,Biotechnology ,Research Article ,Genotype ,General Science & Technology ,Quantitative Trait Loci ,Single-nucleotide polymorphism ,Locus (genetics) ,HapMap Project ,Biology ,Quantitative trait locus ,DIAGNOSIS ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,Rare Diseases ,Genome Analysis Tools ,Genome-Wide Association Studies ,Xanthomatosis ,Humans ,Genetic Predisposition to Disease ,GENOME-WIDE ASSOCIATION ,Polymorphism ,030304 developmental biology ,Genetic association ,Cerebrotendinous ,HEXANUCLEOTIDE REPEAT ,MUTATIONS ,Gene Expression Profiling ,Human Genome ,lcsh:R ,Amyotrophic Lateral Sclerosis ,Neurosciences ,Computational Biology ,Human Genetics ,Brain Disorders ,Genetics of Disease ,Expression quantitative trait loci ,lcsh:Q ,ALS ,Genome Expression Analysis ,CEREBROTENDINOUS XANTHOMATOSIS ,030217 neurology & neurosurgery ,Genome-Wide Association 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. ispartof: PLoS One vol:7 issue:4 ispartof: location:United States status: published
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- 2012
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