Genome wide SNP analysis in Parkinson's disease

National Institute On Aging

Investigators

Linked publications & trials

Abstract

We performed genome wide association studies (GWAS) in Parkinsons Disease (PD) to include a cohort of approximately 60,000 disease cases or disease-related cases, and 1.5 million controls. This work revealed 90 risk loci for disease, redefined the heritable component of Parkinson disease, identified critical tissue and cellular context for genetic risk, and revealed co-morbid conditions. Recent GWAS in PD have been well received as community resources, with over 90 independent genetic risk loci identified. We used diverse collaborative datasets and harmonized this data to yield additional insights, including 12 more novel risk factors and a thorough assessment of the variability of PD genetic risk in populations of diverse continental and genetic ancestries. Additionally, we have generated a code base that utilizes cloud computing resources to harmonize these genetic datasets at population scale and allow for the comparability of genetic data across neurodegenerative diseases with a simple and intelligent user interface with full end-to-end data processing in one single command (In development, https://github.com/dvitale199/GenoTools). CARD Advanced Analytics has also contributed to investigating genetics-related progression factors as well as sex-specific risk factors in this context. Summary data, individual level data (when possible), code and similar resources have been made publicly available in close-to-real time through the Terra.bio platform and GitHub. Current preprint manuscripts resulting from this work include: 1. Kim, J. J. et al. Multi-ancestry genome-wide meta-analysis in Parkinsons disease. medRxiv doi:10.1101/2022.08.04.22278432. 2. Iwaki, H. et al. Differences in the presentation and progression of Parkinsons disease by sex. medRxiv doi:10.1101/2020.04.08.20058370. 3. Blauwendraat, C. et al. Investigation of Autosomal Genetic Sex Differences in Parkinsons disease. medRxiv doi:10.1101/2021.02.09.21250262. 4. Grenn, F. P. et al. Analysis of Y Chromosome Haplogroups in Parkinsons Disease. medRxiv doi:10.1101/2022.02.28.22271633. We have also recently formed the Global Parkinson's Genetics Program (GP2) through the Aligning Science Across Parkinsons (ASAP) initiative. GP2 plans to genotype >150,000 volunteers around the world to further understand the genetic architecture of PD. GP2 aims to increase the number of identified genes, disease-causing mutations, and risk loci for both monogenic and complex PD. We will also prioritize individuals from underrepresented backgrounds in these efforts. A subset of cases will undergo whole-genome sequencing to elucidate genetics contributing to monogenic PD, or long-read DNA sequencing to sequence challenging genomic regions.