title: Mapping of gene expression reveals CYP27A1 as a susceptibility gene for sporadic ALS.
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.
authors.affiliation: Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Frank P
authors.initials: FP
authors.lastname: Diekstra
authors.forename: Christiaan G J
authors.initials: CG
authors.lastname: Saris
authors.forename: Wouter
authors.initials: W
authors.lastname: van Rheenen
authors.forename: Lude
authors.initials: L
authors.lastname: Franke
authors.forename: Ritsert C
authors.initials: RC
authors.lastname: Jansen
authors.forename: Michael A
authors.initials: MA
authors.lastname: van Es
authors.forename: Paul W J
authors.initials: PW
authors.lastname: van Vught
authors.forename: Hylke M
authors.initials: HM
authors.lastname: Blauw
authors.forename: Ewout J N
authors.initials: EJ
authors.lastname: Groen
authors.forename: Steve
authors.initials: S
authors.lastname: Horvath
authors.forename: Karol
authors.initials: K
authors.lastname: Estrada
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivadeneira
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Andre G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: Wim
authors.initials: W
authors.lastname: Robberecht
authors.forename: Peter M
authors.initials: PM
authors.lastname: Andersen
authors.forename: Judith
authors.initials: J
authors.lastname: Melki
authors.forename: Vincent
authors.initials: V
authors.lastname: Meininger
authors.forename: Orla
authors.initials: O
authors.lastname: Hardiman
authors.forename: John E
authors.initials: JE
authors.lastname: Landers
authors.forename: Robert H
authors.initials: RH
authors.lastname: Brown
authors.forename: Aleksey
authors.initials: A
authors.lastname: Shatunov
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Shaw
authors.forename: P Nigel
authors.initials: PN
authors.lastname: Leigh
authors.forename: Ammar
authors.initials: A
authors.lastname: Al-Chalabi
authors.forename: Roel A
authors.initials: RA
authors.lastname: Ophoff
authors.forename: Leonard H
authors.initials: LH
authors.lastname: van den Berg
authors.forename: Jan H
authors.initials: JH
authors.lastname: Veldink
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D053493:Cholestanetriol 26-Monooxygenase / Q000235:genetics*; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D060148:HapMap Project; D006801:Humans; D015810:Linkage Disequilibrium; D009046:Motor Neurons / Q000473:pathology; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics*; D019294:Xanthomatosis, Cerebrotendinous / Q000235:genetics
chemical_list: C506831:CYP27A1 protein, human; D053493:Cholestanetriol 26-Monooxygenase