Oral Presentation GENEMAPPERS 2024

Unveiling peripheral immune dysfunction in Parkinson’s disease through analysis of blood-based mitochondrial DNA copy number (#16)

Longfei Wang 1 2 , Jiru Han 1 2 , Liam G Fearnley 1 2 , Michael Milton 2 3 , Haloom Rafehi 1 2 , Joshua Reid 1 2 4 , Zachary Gerring 1 2 , Shashank Masaldan 2 5 , Tali Lang 6 , Terry P Speed 3 7 , Melanie Bahlo 1 2
  1. Population Health and Immunity Division, The Walter And Eliza Hall Institute Of Medical Research, Parkville, VIC, Australia
  2. Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia
  3. Bioinformatics Division, The Walter And Eliza Hall Institute Of Medical Research, Parkville, VIC, Australia
  4. Epilepsy Research Centre, Department of Medicine (Austin Health), The University of Melbourne, Heidelberg, VIC, Australia
  5. Ubiquitin Signalling Division, The Walter And Eliza Hall Institute Of Medical Research, Parkville, VIC, Australia
  6. Clinical Discovery and Translation, The Walter And Eliza Hall Institute Of Medical Research, Parkville, VIC, Australia
  7. School of Mathematics and Statistics, The University of Melbourne, Parkville, VIC, Australia

Mitochondrial dysfunction plays an important role in Parkinson’s disease (PD), with mitochondrial DNA copy number (mtDNA-CN) emerging as a potential marker for mitochondrial health. Our study aimed to assess the association between blood mtDNA-CN and PD, as well as to uncover the underlying mechanisms.

Introducing mitoCN, a novel mtDNA-CN estimator adjusting for coverage bias, suitable for large-scale whole-genome sequencing (WGS) data, we applied it across six cohorts within the Accelerating Medicines Partnership program for Parkinson's Disease dataset (N=10,418). We investigated the links between blood mtDNA-CN and both PD risk and severity, leveraging comprehensive clinical assessments. Our findings reveal that reduced blood mtDNA-CN levels are associated with heightened PD risk and increased severity of motor symptoms and olfactory dysfunction. However, upon adjusting for blood composition, these associations largely disappeared, indicating a predominant influence of changes in blood variables. Furthermore, using bidirectional Mendelian randomization, we explored causal relationships, finding no evidence of a direct causal relationship between blood mtDNA-CN and PD susceptibility. Thus, even though blood bulk mtDNA-CN correlates with an elevated risk of PD and more severe PD symptoms, our refined analyses and results suggest that peripheral immune dysfunction rather than mitochondrial dysfunction underpins these previously identified associations. Validation of the findings was performed using WGS data from approximately 500,000 participants in the UK Biobank dataset.