Genetics of Parkinson's disease: An introspection of its journey towards precision medicine

Abstract

A substantial proportion of risk for Parkinson's disease (PD) is driven by genetics. Progress in understanding the genetic basis of PD has been significant. So far, highly-penetrant rare genetic alterations in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1 and GBA have been linked with typical familial PD and common genetic variability at 90 loci have been linked to risk for PD. In this review, we outline the journey thus far of PD genetics, highlighting how significant advances have improved our knowledge of the genetic basis of PD risk, onset and progression. Despite remarkable progress, our field has yet to unravel how genetic risk variants disrupt biological pathways and molecular networks underlying the pathobiology of the disease. We highlight that currently identified genetic risk factors only represent a fraction of the likely genetic risk for PD. Identifying the remaining genetic risk will require us to diversify our efforts, performing genetic studies across different ancestral groups. This work will inform us on the varied genetic basis of disease across populations and also aid in fine mapping discovered loci. If we are able to take this course, we foresee that genetic discoveries in PD will directly influence our ability to predict disease and aid in defining etiological subtypes, critical steps for the implementation of precision medicine for PD.

Keywords: Genetics; Parkinson's disease; Post-GWAS era; Risk.

Figure 1.

The genetics of Parkinson disease over time. Red squares represent genome-wide association studies and number of discovered risk loci in brackets. * indicate genes associated with atypical parkinsonism related syndromes. Green squares represent controversial or not widely validated genes linked to typical Parkinson disease

Figure 2

Characterizing the genetic architecture of Parkinson disease.