Genetic Risk Profiling in Parkinson's Disease and Utilizing Genetics to Gain Insight into Disease-Related Biological Pathways.

Ashley Hall,John P Quinn,Sara Bandres-Ciga,Monica Diez-Fairen,Kimberley J Billingsley,Kimberley J Billingsley

doi:10.3390/ijms21197332

Abstract

Parkinson’s disease (PD) is a complex disorder underpinned by both environmental and genetic factors. The latter only began to be understood around two decades ago, but since then great inroads have rapidly been made into deconvoluting the genetic component of PD. In particular, recent large-scale projects such as genome-wide association (GWA) studies have provided insight into the genetic risk factors associated with genetically ‘’complex’’ PD (PD that cannot readily be attributed to single deleterious mutations). Here, we discuss the plethora of genetic information provided by PD GWA studies and how this may be utilized to generate polygenic risk scores (PRS), which may be used in the prediction of risk and trajectory of PD. We also comment on how pathway-specific genetic profiling can be used to gain insight into PD-related biological pathways, and how this may be further utilized to nominate causal PD genes and potentially druggable therapeutic targets. Finally, we outline the current limits of our understanding of PD genetics and the potential contribution of variation currently uncaptured in genetic studies, focusing here on uncatalogued structural variants.

Highlights

Parkinson’s disease (PD) is characterized by a loss of dopaminergic neurons, in the substantia nigra, and widespread accumulation of intracellular α-synuclein protein aggregates such as Lewy bodies
We discuss the plethora of genetic information provided by PD genome-wide association (GWA) studies and how this may be utilized to generate polygenic risk scores (PRS), which may be used in the prediction of risk and trajectory of PD
We outline the current limits of our understanding of PD genetics and the potential contribution of variation currently uncaptured in genetic studies, focusing here on uncatalogued structural variants

Summary

Parkinson’s Disease Genetics

Parkinson’s disease (PD) is characterized by a loss of dopaminergic neurons, in the substantia nigra, and widespread accumulation of intracellular α-synuclein protein aggregates such as Lewy bodies. Epidemiology studies pointed to exposure to viruses and neurotoxins such as MPTP [4]; perhaps most famous was the strong association between the 1918 influenza pandemic and the increased rates of post-encephalitic parkinsonism that followed This non-genetic basis of PD was supported by the first cross-sectional twin studies of the disease [5]. The premise of a GWA study is to compare the genotypes of many individuals, often in a case vs control setup, and determine which common genetic variants, typically single nucleotide variants (SNVs), are consistently associated with a trait The power of this analysis increases with the number of participants, as this allows the contributions of relatively low-risk disease-associated variants to be detected. Despite the huge success over the last decade in identifying PD genetic risk factors, we outline the current gaps in our understanding of PD genetics, with a focus on the contribution of the uncharacterized parts of the human genome, namely, uncatalogued structural variants

Genetic risk Profiling in Parkinson’s Disease

Analytical Methods for Gene Prioritization

Findings

Future Directions