Establishing the role of rare coding variants in known Parkinson's disease risk loci

Neurobiol Aging. 2017 Nov;59:220.e11-220.e18. doi: 10.1016/j.neurobiolaging.2017.07.009. Epub 2017 Aug 2.


Many common genetic factors have been identified to contribute to Parkinson's disease (PD) susceptibility, improving our understanding of the related underlying biological mechanisms. The involvement of rarer variants in these loci has been poorly studied. Using International Parkinson's Disease Genomics Consortium data sets, we performed a comprehensive study to determine the impact of rare variants in 23 previously published genome-wide association studies (GWAS) loci in PD. We applied Prix fixe to select the putative causal genes underneath the GWAS peaks, which was based on underlying functional similarities. The Sequence Kernel Association Test was used to analyze the joint effect of rare, common, or both types of variants on PD susceptibility. All genes were tested simultaneously as a gene set and each gene individually. We observed a moderate association of common variants, confirming the involvement of the known PD risk loci within our genetic data sets. Focusing on rare variants, we identified additional association signals for LRRK2, STBD1, and SPATA19. Our study suggests an involvement of rare variants within several putatively causal genes underneath previously identified PD GWAS peaks.

Keywords: Common risk loci; Parkinson's disease; Rare variants; Variant aggregation test; Whole exome sequencing.

MeSH terms

  • Datasets as Topic
  • Genetic Loci / genetics*
  • Genetic Predisposition to Disease / genetics*
  • Genetic Variation / genetics*
  • Genome-Wide Association Study*
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics
  • Membrane Proteins / genetics
  • Mitochondrial Proteins / genetics
  • Muscle Proteins / genetics
  • Parkinson Disease / genetics*
  • Risk
  • Seminal Plasma Proteins / genetics


  • Membrane Proteins
  • Mitochondrial Proteins
  • Muscle Proteins
  • SPATA19 protein, human
  • Seminal Plasma Proteins
  • Stbd1 protein, human
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2