Elsevier

The Lancet Neurology

Volume 19, Issue 2, February 2020, Pages 170-178
The Lancet Neurology

Review
The genetic architecture of Parkinson's disease

https://doi.org/10.1016/S1474-4422(19)30287-XGet rights and content

Summary

Parkinson's disease is a complex neurodegenerative disorder for which both rare and common genetic variants contribute to disease risk, onset, and progression. Mutations in more than 20 genes have been associated with the disease, most of which are highly penetrant and often cause early onset or atypical symptoms. Although our understanding of the genetic basis of Parkinson's disease has advanced considerably, much remains to be done. Further disease-related common genetic variability remains to be identified and the work in identifying rare risk alleles has only just begun. To date, genome-wide association studies have identified 90 independent risk-associated variants. However, most of them have been identified in patients of European ancestry and we know relatively little of the genetics of Parkinson's disease in other populations. We have a limited understanding of the biological functions of the risk alleles that have been identified, although Parkinson's disease risk variants appear to be in close proximity to known Parkinson's disease genes and lysosomal-related genes. In the past decade, multiple efforts have been made to investigate the genetic architecture of Parkinson's disease, and emerging technologies, such as machine learning, single-cell RNA sequencing, and high-throughput screens, will improve our understanding of genetic risk.

Introduction

The burden of Parkinson's disease is a growing health-care problem, with a global prevalence that is expected to double from 6·2 million cases in 2015 to 12·9 million cases by 2040.1 Clinically, Parkinson's disease is defined as a progressive movement disorder, although the presentation of non-motor symptoms can also be severe. Parkinson's disease has a long prodromal phase with features such as anosmia, constipation, and sleep disturbance.2, 3 Pathologically, Parkinson's disease is characterised by a loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies in the midbrain. Lewy bodies are protein aggregates consisting of many proteins, including α-synuclein (encoded by the SNCA gene). Parkinson's disease is the most common synucleinopathy; other synucleinopathies are multiple system atrophy and dementia with Lewy bodies, and these are clinically, and perhaps genetically, overlapping diseases.4, 5

Advancing age is the greatest risk factor for Parkinson's disease, but both environment and genetics are thought to affect disease risk and progression. Although studying the environmental contribution to disease is complex, potential associations between Parkinson's disease and several environmental traits have been found, including pesticide exposure, smoking, and caffeine intake.6, 7, 8 Genetic contributors to Parkinson's disease exist across a continuum, ranging from DNA variants that are highly penetrant (ie, causal) to variants that individually exert a small increase in lifetime risk of disease. Genetic risk is often divided into categories: rare DNA variants with high effect sizes, which are typically associated with monogenic or familial Parkinson's disease; and more common, smaller effect variants, which are usually identified in apparently sporadic Parkinson's disease.

Rare disease-causing DNA variants were historically identified using linkage studies in large families with Parkinson's disease, and have more recently been identified with next-generation sequencing techniques, such as exome and genome sequencing. The common genetic components of Parkinson's disease have mostly been identified using genome-wide association studies (GWASs) and to date 90 independent risk signals have been identified.9 In this Review, we describe current knowledge of Parkinson's disease genetics, including the most recent developments in the field, and discuss our predictions for the future of Parkinson's disease genetics.

Section snippets

Monogenic Parkinson's disease

For Parkinson's disease, the term monogenic is a useful oversimplification. Although several highly penetrant rare variants are linked to Parkinson's disease (resulting in so-called monogenic Parkinson's disease), the presentation of the disease is likely to be affected by other factors, including both genetic and non-genetic factors. In some carriers of highly penetrant variants, the disease will not manifest (known as incomplete penetrance), and for those with the disease, the age of onset,

Diversifying genetics

Genetic diversity is a major challenge in the field of Parkinson's disease genetics. Similar to many other scientific fields, the majority of research has been done in individuals with mainly European ancestry.50 This lack of diversity means that genetic risk score predictions for disease might not be globally generalisable.51

Several notable findings have been reported in non-European populations; for instance, certain GBA variants and LRRK2 Gly2019Ser are highly enriched in the Ashkenazi

Conclusion

Understanding the genetic factors that influence Parkinson's disease risk, onset, and progression is crucial to developing treatments that might slow or stop disease progression. To date, many genes and GWAS loci have been identified that contribute to the development of Parkinson's disease. We need to continue this search for genetic risk factors, while also making a concerted, coordinated effort to understand the consequences of these discoveries at the molecular and biological levels. This

Search strategy and selection criteria

References for this Review were identified by searches of PubMed and bioRxiv, from database inception to April 1, 2019, and of the reference lists of relevant articles. The search terms used were: “Parkinson” or “Parkinson's disease” in combination with “genetics”, “gene”, “genome-wide”, “meta-analysis”, or “GWAS”. No language restrictions were applied. The final reference list was generated on the basis of relevance to the topics covered in this Review.

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