title: Whole exome sequencing of rare variants in EIF4G1 and VPS35 in Parkinson disease.
abstract: OBJECTIVE
  Recently, vacuolar protein sorting 35 (VPS35) and eukaryotic translation initiation factor 4 gamma 1 (EIF4G1) have been identified as 2 causal Parkinson disease (PD) genes. We used whole exome sequencing for rapid, parallel analysis of variations in these 2 genes.
  
  
  METHODS
  We performed whole exome sequencing in 213 patients with PD and 272 control individuals. Those rare variants (RVs) with <5% frequency in the exome variant server database and our own control data were considered for analysis. We performed joint gene-based tests for association using RVASSOC and SKAT (Sequence Kernel Association Test) as well as single-variant test statistics.
  
  
  RESULTS
  We identified 3 novel VPS35 variations that changed the coded amino acid (nonsynonymous) in 3 cases. Two variations were in multiplex families and neither segregated with PD. In EIF4G1, we identified 11 (9 nonsynonymous and 2 small indels) RVs including the reported pathogenic mutation p.R1205H, which segregated in all affected members of a large family, but also in 1 unaffected 86-year-old family member. Two additional RVs were found in isolated patients only. Whereas initial association studies suggested an association (p = 0.04) with all RVs in EIF4G1, subsequent testing in a second dataset for the driving variant (p.F1461) suggested no association between RVs in the gene and PD.
  
  
  CONCLUSIONS
  We confirm that the specific EIF4G1 variation p.R1205H seems to be a strong PD risk factor, but is nonpenetrant in at least one 86-year-old. A few other select RVs in both genes could not be ruled out as causal. However, there was no evidence for an overall contribution of genetic variability in VPS35 or EIF4G1 to PD development in our dataset.
authors: John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, FL, USA.
authors: Karen
authors: K
authors: Nuytemans
authors: Guney
authors: G
authors: Bademci
authors: Vanessa
authors: V
authors: Inchausti
authors: Amy
authors: A
authors: Dressen
authors: Daniel D
authors: DD
authors: Kinnamon
authors: Arpit
authors: A
authors: Mehta
authors: Liyong
authors: L
authors: Wang
authors: Stephan
authors: S
authors: Züchner
authors: Gary W
authors: GW
authors: Beecham
authors: Eden R
authors: ER
authors: Martin
authors: William K
authors: WK
authors: Scott
authors: Jeffery M
authors: JM
authors: Vance
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D039603:Eukaryotic Initiation Factor-4G / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000175:diagnosis / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods; D033921:Vesicular Transport Proteins / Q000235:genetics*
chemical_list: C113920:EIF4G1 protein, human; D039603:Eukaryotic Initiation Factor-4G; C419573:VPS35 protein, human; D033921:Vesicular Transport Proteins