Learn about the the past, present and future of Parkinson’s Disease in this course. Building on that foundation, the course then covers the basic concepts in human genetics before discussing monogenic causes of PD, current clinical setting of PD, and modern advancements in the field. The course wraps up by looking at the genetic progression, genetics of atypical parkinsonism and advances and challenges of the genetics in underrepresented populations.
Modules
Over the last two decades, we have witnessed a revolution in the field of Parkinson’s disease (PD) genetics. Great advances have been made which have subsequently led to an improved understanding of the molecular pathways involved in disease pathogenesis.
In this module you will:
- Be introduced to the history of Parkinson’s disease genetics from its origins.
- Learn about the major genetic discoveries associated with PD by Mendelian inheritance.
- Learn about molecular pathways involved on PD etiology that are uncovered by genetics, and the differences in the neuropathology of genetic mutation carriers.
- Gain insight into the future of PD genetics.
This module covers basic concepts in human genetics, which will provide you with the necessary background for the next modules in this course.
In this module you will:
- Be reminded of the structure and function of DNA.
- Learn about different genetic variations and forms of genetic inheritance.
- Learn about different types of genetic studies.
- Gain an understanding of different properties and applications of genetic variant analyses.
This module will teach you different approaches that can be followed to identify monogenic causes of Parkinson’s disease (PD). In this module you will:
- Learn the role of familial studies in different scenarios, starting from traditional mapping studies, which include linkage analysis and homozygosity mapping.
- Gain an understanding of the use of trio studies that are used to identify both de novo and recessive variants.
- Understand the role of publicly available datasets and prediction tools when filtering potentially pathogenic variants.
Parkinson’s disease (PD) genetics has made impressive progress over the last two decades. It’s important to understand how this progress has improved PD diagnosis, prognosis, and management in a clinical setting.
In this module you will:
- Learn about different categories of genetic testing.
- Learn how to choose the right type of genetic testing.
- Learn how to correctly interpret the outcome of a genetic test.
- Come to understand the importance of pre and post-test genetic counseling.
Since the discovery of the structure of DNA in the 1950s, geneticists have made new discoveries at a breathtaking rate. The publication of the sequence of the entire human genome in 2001 by the Human Genome Project marked an exciting starting point for the study of the genomics of complex diseases.
In this module you will:
- Learn how advances in technology have improved the cost and scale of genome characterization through sequencing and genotyping.
- Learn how these technologies empower clinical diagnostics and other aspects of medical care.
- Gain an understanding of the current technologies used to find risk and causative alleles in Parkinson’s disease genetics, specifically genotyping arrays and next-generation sequencing methods.
GWAS stands for genome-wide association studies. It’s used to test common genetic variant and look for genotype/phenotype correlations, and identify genetic variants associated with a disease.
In this module you will:
- Learn about gold standard metrics, along with technical challenges and limitations of GWAS.
- Learn about different types of GWAS for both binary and continuous outcomes, how to account for relatedness and varying population ancestries.
- Learn about the concept of pleomorphic risk loci.
- Come to understand the differences between fixed versus random effects.
- Learn about risk predictions.
- See examples of future directions in the Parkinson’s disease genetics research field.
Parkinson’s disease (PD) is a progressive condition, so symptoms will worsen over time. There is significant variability between individuals in the rate of progression, as well as the age of onset of PD.
In this module you will:
- Be introduced to progression in PD through examples of key longitudinal cohort studies.
- Gain an understanding of the biology of progression and age at onset in PD.
- Be introduced to measurements and methods to capture the progression of PD.
- Learn about analytical methods to determine the contribution of disease-modifying genetic factors
- Learn about genetic factors reported to be associated with PD progression (genotype-phenotype association).
Research into atypical parkinsonism syndromes is a relatively understudied field. There are increasingly recognized clinical and molecular overlaps and similarities between various parkinsonism syndromes, and examining these conditions provides an opportunity to understand a broader spectrum of neurodegenerative diseases.
In this module you will:
- Learn basic definitions of terminology used by clinicians.
- Be introduced to the most common atypical parkinsonism syndromes.
- Learn how the complex disease model is applied to these syndromes.
- Gain insight into the genetic architecture of these conditions.
Lack of ethnic diversity is a systemic issue in genetic studies. But genetic diversity can be used to better understand the genetics of a disease, and efforts such as GP2 are aiming to provide insights applicable in the Parkinson’s disease landscape.
In this module you will:
- Learn that research so far has been focused on individuals of European ancestry.
- Learn about the concept of genetic admixture.
- Come to understand the difference between global and local ancestry, and how this impacts the way we should look at disease risk.
- Be introduced to methods including trans-ethnic meta-analysis, fine mapping and admixture mapping.
Mendelian randomization (MR) is a method in genetic epidemiology help us infer causality from observational associations. It can help mitigate the chance of confounding and reverse causation.
In this module you will:
- Learn about MR, including its origins, advantages and limitations.
- Be introduced to the underlying instrumental variable assumptions which apply to MR.
- Learn about using multiple genetic variants as proxies for an exposure of interest, including the handling of pleiotropy and the running of sensitivity analyses.
- Be introduced to extensions to the MR concept, including cis-MR and the incorporation of quantitative trait locus (QTL) data to look at functional consequences.
Over the past 15 years, GWAS has allowed us to associate genetic loci to various diseases and other phenotypes in the Parkinson’s disease genetics field. Current identified GWAS signals explain about ⅓ of the total heritability of disease. But there are a number of things that GWAS doesn’t enable us to explore, including translating GWAS loci to functional understanding of disease. This is where fine-mapping, colocalization, and data integration come in.
In this module you will:
- Be introduced to the concepts of fine-mapping and colocalization.
- See useful examples of fine-mapping and colocalization.
- Learn about drawbacks and challenges of these two approaches.
- Learn about the future of data integration with a main focus on the multi-omics approach.
Developing safe and effective therapeutics is a key challenge, especially for drugs targeting central nervous system indications. However, genetics can help predict success in the clinic, with drugs targeting proteins with a genetic connection to disease more likely to be approved.
In this module you will:
- Learn how human genetics informs the drug discovery process.
- Gain an insight into target identification, to therapeutic strategy, to biomarker development and safety evaluation.
- See practical examples of these stages of drug discovery, with LRRK2 as an example gene in the Parkinson’s disease genetics field.
Throughout this course, you will have come across single nucleotide variants (SNVs), also known as single nucleotide polymorphisms (SNPs). However another form of genetic variation, structural variants (SVs), are yet to be systematically cataloged in the human genome.
In this module you will:
- Be introduced to structural variants (SVs) in more details.
- Learn about different classes of SVs in the human genome.
- Learn about variants found to be causative of different forms of monogenic Parkinson’s disease and parkinsonism.
- Come to understand why it is important to identify the contribution of SVs to genetically complex Parkinson’s disease.
- Learn about the challenges in detecting and calling SVs in current short-read sequencing datasets.
- Be introduced to the current tools that accurately call these variants genome-wide.
