Parkinson's Disease is Predominantly a Genetic Disease

Abstract

The discovery of a pathogenic variant in the alpha-synuclein (SNCA) gene in the Contursi kindred in 1997 indisputably confirmed a genetic cause in a subset of Parkinson's disease (PD) patients. Currently, pathogenic variants in one of the seven established PD genes or the strongest known risk factor gene, GBA1, are identified in ∼15% of PD patients unselected for age at onset and family history. In this Debate article, we highlight multiple avenues of research that suggest an important - and in some cases even predominant - role for genetics in PD aetiology, including familial clustering, high rates of monogenic PD in selected populations, and complete penetrance with certain forms. At first sight, the steep increase in PD prevalence exceeding that of other neurodegenerative diseases may argue against a predominant genetic etiology. Notably, the principal genetic contribution in PD is conferred by pathogenic variants in LRRK2 and GBA1 and, in both cases, characterized by an overall late age of onset and age-related penetrance. In addition, polygenic risk plays a considerable role in PD. However, it is likely that, in the majority of PD patients, a complex interplay of aging, genetic, environmental, and epigenetic factors leads to disease development.

Keywords: GBA1; LRRK2; PRKN; Parkinson’s disease; environment; epigenetic; familial; gene-environment interactions; genetics; monogenic; pandemic; polygenic; progression.

Fig. 1

Screenshot from the MDSGene website (https://www.mdsgene.org, accessed on 5 November 2023), here depicting, as an example, the updated statistics on PARK-PRKN cases reported worldwide with individual-level data (almost 1,500 cases). The website also provides curated data regarding patients’ clinical characteristics and the pathogenicity classification of genetic variants.

Fig. 2

Screenshot from the Global Parkinson’s Genetics Program (GP2) website (https://gp2.org, accessed on 5 November 2023), depicting the updated statistics on an ever-growing number of contributing sites and samples.