Poster Presentation 16th Asian Conference on Transcription 2019

A Novel Insight into the Regulation of GBA in Parkinson’s Disease (1138)

Sophie L Farrow 1 , William Schierding 1 , Sara Qubisi 2 , Alan Davidson 2 , Jo Perry 1 , Antony Cooper 3 4 , Justin O'Sullivan 1
  1. Liggins Institute , University of Auckland, Auckland, New Zealand
  2. Molecular Medicine and Pathology , University of Auckland, Auckland, New Zealand
  3. Division of Neuroscience, Garvan Institute of Medical Research, Sydney, New South Wales, Australia
  4. St Vincent's Clinical School, UNSW Sydney, Sydney, New South Wales, Australia

Parkinson’s disease (PD) is a complex neurodegenerative illness affecting more than 7 million individuals worldwide. The majority of cases are idiopathic, yet evidence increasingly points to a strong genetic component. Mutations within the GBA gene, which impact GCase activity, are the greatest genetic risk factor for familial PD. However, reduced GCase activity has been identified in idiopathic PD patients lacking GBA mutations, consistent with alternative disease mechanisms. We hypothesised that enhancers located at the GBA locus and throughout the 3D genome regulate GBA and modifier genes that impact on alternative mechanisms of PD development. We utilised an algorithm that uses information on the 3D organization of the genome to screen variants within the GBA locus for regulatory potential. Seventy-three variants were identified that collectively regulate 143 genes. We subsequently performed a genome-wide search of 31,471,836 SNPs for regulatory activity on GBA in PD relevant tissues and identified a trans-acting regulatory region in ELFN2 (chr.22) that downregulates GBA expression in the substantia nigra (SN). We contend that this regulatory region contributes to the observed selective reduction of GBA/GCase activity in the SN of idiopathic PD patients lacking GBA missense mutations. Our results illustrate that GBA is a hub of regulatory activity, fundamental to PD pathology. Expanding these efforts to functional validation of the regulatory regions will quantify the effects and their potential for disease stratification.