Genome wide SNP analysis in Parkinson's disease

$1,189,490ZIAFY2023AGNIH

National Institute On Aging

Investigators

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Abstract

We performed genome wide association studies in 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, has redefined the heritable component of Parkinson disease, has identified critical tissue and cellular context for genetic risk, and revealed co-morbid conditions. Recent GWAS in Parkinsons disease have been well received as community resources, with over 90 independent genetic risk loci identified. We have used diverse collaborative datasets and harmonized this data to yield additional insights including twelve more novel risk factors and a thorough assessment of the variability of Parkinson's 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 intelligible user interface with full end-to-end data processing in one single command. CARD Advanced Analytics has also contributed to investigating genetics related progression factors as well as sex specific risk factors in this context. As with all MGS and CARD projects in this research space, 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. We have 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 Parkinson's disease. 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. A recent study from this team, a companion to our ongoing work in Alzheimers disease, includes an adaptation of the codebase to carry out a multi-ancestry meta-analysis of Parkinsons disease.

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