There is growing indication that the immune system plays a role in the development and progression of Parkinson’s disease with recent genome-wide association studies identifying independent risk variants within the genes responsible for the regulation of the immune system, particularly HLA and KIR. The central element of this project is to apply next generation sequencing methods and a validated analytical pipeline to assess the association of sequence variation in the HLA and KIR loci with risk to Parkinson's disease.
Our goal is to characterize the full spectrum of HLA and KIR sequence variants driving susceptibility to Parkinson’s disease using next generation sequencing and a validated analytical pipeline. We will genotype 1,320 patients and 300 controls. Application of modern sequencing methodologies to large and well-characterized datasets, coupled with state of the art bioinformatics and analytical approaches will permit us to fully appreciate the impact of HLA/KIR variation in Parkinson’s disease.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
The socioeconomic and personal consequences of brain disorders are staggering, with many published surveys unequivocally concluding that chronic neurological diseases are very costly to the individual, heath care systems, and society in general. Despite significant progress in the management of many of these diseases, we are still missing complete and coherent models of pathogenesis and as a result, the repertoire of available therapies is imperfect. Recent advances in genomic sciences have set in place the foundation for understanding the role of inflammation and decoding the rules of inheritable risk for chronic neurological diseases, which may translate into improved prognosis and therapeutic options. We will develop improved methodological protocols to effectively address the inherent challenges of Next Generation Sequencing (NGS)-based HLA/KIR genotyping, and share both the methodological approach and the wealth of results generated in this study with the broader research community, adding significant value to publicly accessible genomic datasets.
Next Steps for Development:
Our investigation of the relationship between HLA and KIR variants with the risk of Parkinson’s disease has strong potential to reveal biological mechanisms involved in movement disorders, and to provide an informative analysis of genetic pleiotrophy in neurological diseases.
Progress in understanding the genetic underpinnings of multi-factorial neurological diseases has been aided by the discovery of hundreds of susceptibility DNA variants influencing susceptibility. Interestingly, a recent survey revealed that nearly 20% of these risk genetic variants overlap across unrelated diseases, including neuro-inflammatory, neurodegenerative, and movement disorders. In some cases, the same variants show association with multiple traits, whereas in other cases, the associations are mediated by distinct but nearby genetic markers. An important component of this genetic commonality resides in the short arm of chromosome 6, where a genetic complex known as the Major histocompatibility Complex or MHC is located. HLA genes within the MHC are known to code for proteins that operate as important master-switches of the immune response.
Contemporary technological improvements have significantly improved our ability to examine genetic variation as it relates to human disease. This project has as its primary goal to identify and characterize with high resolution and accuracy the repertoire of HLA genes that predispose to Parkinson’s disease (PD). We performed deep sequencing across eleven HLA genes in DNA samples from individuals affected with PD who contributed blood samples to the Michael J Fox and NIH repositories. We found that both, protection and risk is partially attributable to a specific variant in the HLA-DRB1 gene, providing a framework for understanding the nature of the immune component in PD pathogenesis.