Oral Presentation GENEMAPPERS 2024

Investigating causal effects of blood circulating proteins on Parkinson’s disease risk in Asians and Europeans (#4)

Amanda Wei-Yin Lim 1 2 , Jia-Nee Foo 3 4 , Shen-Yang Lim 5 6 , Stuart MacGregor 1 2 , Miguel E Renteria 1 2 7 , Jue-Sheng Ong 1 2
  1. QIMR Berghofer, Herston, QUEENSLAND, Australia
  2. Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
  3. Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore
  4. Human Genetics, Genome Institute of Singapore, A*STAR, Singapore
  5. Division of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Wilayah Persekutuan KL, Malaysia
  6. The Mah Pooi Soo & Tan Chin Nam Centre for Parkinson's & Related Disorders, University of Malaya, Kuala Lumpur, Wilayah Persekutuan KL, Malaysia
  7. Global Brain Health Institute, University of California, San Francisco, CA, USA

Background
Recent genome-wide association studies (GWAS) identified 11 loci associated with Parkinson’s disease (PD) susceptibility in Asians, yet their mechanisms remain unclear. Compared to European GWAS, which found 90 loci explaining 16-36% of the single-nucleotide polymorphism heritability, these loci represent only a small fraction. To explore ancestry-based differences, we integrated PD GWAS results with ancestry-specific protein quantitative trait loci (pQTL) data to identify common and unique PD risk proteins in Asians and Europeans.
Methods
We evaluated the causal influence of blood circulating proteins on PD risk using a two-sample Mendelian randomisation (MR) framework. For Asians, plasma proteomics from Han Chinese and East Asians (236 unique proteins, 3,220 participants) were combined with a PD GWAS in Asians (6,724 cases, 24,851 controls). For Europeans, we used the UK Biobank plasma proteomics dataset (2,398 unique proteins, 54,219 participants) alongside the latest PD GWAS in Europeans (37,688 cases, 18,618 proxy-cases, 1.4 million controls).
Results
In Asians, six proteins were identified to causally influence PD risk, after Bonferroni correction [APOM (OR=1.32, p=1.33x10-6), APOA1 (OR=1.22, p=1.00x10-4), BST1 (OR=1.18, p=1.50x10-6), C4A (OR=0.83, p=2.51x10-6), PM20D1 (OR=0.92, p=5.88x10-5), and TOP1 (OR=0.90, 5.88x10-5), per standard deviation increase in genetically predicted gene expression]. While four proteins showed consistent effects in Europeans, none reached statistical significance. APOM and APOA1 are linked to disease gene regulation and earlier PD onset, BST1 to dopaminergic vulnerability, C4A to immune processes, and PM20D1 to oxidative stress.
Conclusions
Our findings highlight potential gene-protein-PD association differences between Asians and Europeans, potentially impacting the transferability of biomarkers and preventative strategies across ancestries. However, caution is warranted due to GWAS power differences. Validation with multi-ancestry pQTL models and larger GWAS in underrepresented populations are needed.