title: EIF4G1 is neither a strong nor a common risk factor for Parkinson's disease: evidence from large European cohorts.
abstract: BACKGROUND
  Missense mutations in the eukaryotic translation initiation factor 4-γ 1 (EIF4G1) gene have previously been implicated in familial Parkinson's disease (PD). A large PD family with autosomal-dominant segregation showed a heterozygous missense mutation and additional patients were found to have unique sequence variants that have not been observed in controls. Subsequent studies have reported contradictory findings.
  
  
  METHODS
  We assessed the relevance of EIF4G1 mutations in a European cohort of 2146 PD patients. Of these, 2051 sporadic PD patients were screened for the reported p.Ala502Val and p.Arg1205His mutations. In addition, the complete coding region of EIF4G1 was directly sequenced in 95 familial PD patients with autosomal-dominant inheritance. Moreover, we imputed the p.Arg1205His substitution and tested for association with PD in the Icelandic population (93 698 samples).
  
  
  RESULTS
  We did not observe the presence of the p.Ala502Val substitution in our cohort; however, the p.Arg1205His mutation was identified in one sporadic PD patient. The same mutation was also found in 76 Icelandic subjects older than 65 years using haplotype imputing. Only five of these subjects reported PD symptoms (OR 1.3, p=0.50). Thus, if causal, the p.Arg1205His EIF4G1 mutation has a low penetrance or a late onset manifestation. A novel variant p.Arg566Cys found in a patient with familial PD did not cosegregate with PD in all three affected siblings. All further recently published EIF4G1 mutations found in our cohort are likely to be benign polymorphisms.
  
  
  CONCLUSIONS
  This is the largest genetic study of EIF4G1 mutations in PD. Our data do not support the EIF4G1 gene as a high-risk PD locus, neither for the familial nor the sporadic condition. Furthermore, the p.Arg1205His mutation is not significantly associated with increased risk of PD in the Icelandic population. Therefore, caution should be exercised when interpreting EIF4G1 genotyping results in isolated patients and PD families. In summary, diagnostic testing of EIF4G1 should not be recommended in clinical settings.
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Huttenlocher
authors.affiliation: Center for Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany Department of Clinical and Experimental Neuroscience, Luxembourg Center for Systems Biomedicine (LCSB), University of Luxembourg, Luxembourg.
authors.forename: Rejko
authors.initials: R
authors.lastname: Krüger
authors.affiliation: Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Capetian
authors.affiliation: Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Lohmann
authors.affiliation: Center for Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Brockmann
authors.affiliation: Gertrudis-Kliniken, Biskirchen, Germany.
authors.forename: Ilona
authors.initials: I
authors.lastname: Csoti
authors.affiliation: Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Klein
authors.affiliation: Center for Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Berg
authors.affiliation: Center for Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gasser
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Bonin
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Riess
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
authors.forename: Peter
authors.identifier: http://orcid.org/0000-0001-9414-4555
authors.initials: P
authors.lastname: Bauer
mesh_terms: D001483:Base Sequence; D015331:Cohort Studies; D039603:Eukaryotic Initiation Factor-4G / Q000235:genetics*; D005060:Europe / Q000453:epidemiology; D005799:Genes, Dominant / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D010300:Parkinson Disease / Q000453:epidemiology* / Q000235:genetics*; D012307:Risk Factors; D017422:Sequence Analysis, DNA
chemical_list: C113920:EIF4G1 protein, human; D039603:Eukaryotic Initiation Factor-4G
keywords: Parkinson-s disease