Poster Presentation 40th Annual Lorne Genome Conference 2019

Systematic functional validation of Parkinson's disease GWAS identifies MCMBP as a potential therapeutic target (#233)

Lisa Oyston 1 , Hagen Blankenburg 2 , Georgia Kafer 3 , Christian Weichenberger 2 , Marloes Van Roijen 4 , Greg Sutherland 4 , Anthony Cesare 3 , Andrew Hicks 2 , Greg Neely 1
  1. Dr John and Anne Chong Lab for Functional Genomics, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia
  2. Institute for Biomedicine, Eurac Research, Bolzano, Italy
  3. Children's Medical Research Institute, Sydney, NSW, Australia
  4. Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia

While thousands of genome-wide association studies (GWAS) have been published, large-scale functional validation of these efforts is lacking. Here we systematically tested disease modifying activity for 802 conserved genes associated with Parkinson’s disease (PD). From this we confirm that GWAS p-value strongly correlates with the frequency of functional disease genes. Out of all candidates tested, only one gene, CG3430, a homolog of the human gene MCMBP, blocked disease progression in multiple paradigms. MCMBP is a binding partner of the MCM complex, which plays a role in DNA replication and is associated with DNA damage and repair. Targeting MCMBP could suppress DNA damage induced by alpha synuclein (aSyn) in both fly and human cells.  Importantly, MCMBP expression was upregulated in the substantia nigra of patients with PD, but not control brains. Together, we provide functional validation for GWAS as a means of identifying disease modifying genes, and highlight MCMBP as a critical mediator of aSyn-dependent DNA damage during PD.