Whole-genome sequencing suggests mechanisms for 22q11.2 deletion-associated Parkinson's disease

PLoS One. 2017 Apr 21;12(4):e0173944. doi: 10.1371/journal.pone.0173944. eCollection 2017.


Objectives: To investigate disease risk mechanisms of early-onset Parkinson's disease (PD) associated with the recurrent 22q11.2 deletion, a genetic risk factor for early-onset PD.

Methods: In a proof-of-principle study, we used whole-genome sequencing (WGS) to investigate sequence variants in nine adults with 22q11.2DS, three with neuropathologically confirmed early-onset PD and six without PD. Adopting an approach used recently to study schizophrenia in 22q11.2DS, here we tested candidate gene-sets relevant to PD.

Results: No mutations common to the cases with PD were found in the intact 22q11.2 region. While all were negative for rare mutations in a gene-set comprising PD disease-causing and risk genes, another candidate gene-set of 1000 genes functionally relevant to PD presented a nominally significant (P = 0.03) enrichment of rare putatively damaging missense variants in the PD cases. Polygenic score results, based on common variants associated with PD risk, were non-significantly greater in those with PD.

Conclusions: The results of this first-ever pilot study of WGS in PD suggest that the cumulative burden of genome-wide sequence variants may contribute to expression of early-onset PD in the presence of threshold-lowering dosage effects of a 22q11.2 deletion. We found no evidence that expression of PD in 22q11.2DS is mediated by a recessive locus on the intact 22q11.2 chromosome or mutations in known PD genes. These findings offer initial evidence of the potential effects of multiple within-individual rare variants on the expression of PD and the utility of next generation sequencing for studying the etiology of PD.

MeSH terms

  • Adult
  • Chromosomes, Human, Pair 22*
  • Female
  • Genetic Predisposition to Disease
  • High-Throughput Nucleotide Sequencing / methods*
  • Humans
  • Male
  • Middle Aged
  • Parkinson Disease / genetics*

Grants and funding

This work was supported by the Canadian Institutes of Health Research (A.S.B, MOP #97800, MOP #111238), Canada Research Chairs program (A.S.B), a Brain Canada Mental Health Training Award (N.J.B), a Canadian Institutes of Health Research Frederick Banting and Charles Best Canada Graduate Scholarship (N.J.B), and Science and Technology Innovation Centre funding from Genome Canada/Ontario Genomics Institute (D.M.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.