Mapping of gene expression reveals CYP27A1 as a susceptibility gene for sporadic ALS

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. LandersRobert H. Brown, Aleksey Shatunov, Christopher E. Shaw, P. Nigel Leigh, Ammar Al-Chalabi, Roel A. Ophoff, Leonard H. van den Berg, Jan H. Veldink

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

45 Citations (Scopus)


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.

Original languageEnglish
Article number35333
Pages (from-to)e35333
Number of pages9
JournalPL o S One
Issue number4
Publication statusPublished - 11 Apr 2012


  • Amyotrophic Lateral Sclerosis
  • Cholestanetriol 26-Monooxygenase
  • Gene Expression Profiling
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Genotype
  • HapMap Project
  • Humans
  • Linkage Disequilibrium
  • Motor Neurons
  • Pedigree
  • Polymorphism, Single Nucleotide
  • Quantitative Trait Loci
  • Xanthomatosis, Cerebrotendinous
  • N.I.H., Extramural
  • Non-U.S. Gov't


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