Although the causes of Parkinson's disease (PD) are thought to be primarily environmental, recent studies suggest that a number of genes influence susceptibility. Using targeted case recruitment and online survey instruments, we conducted the largest case-control genome-wide association study (GWAS) of PD based on a single collection of individuals to date (3,426 cases and 29,624 controls). We discovered two novel, genome-wide significant associations with PD–rs6812193 near SCARB2 (, ) and rs11868035 near SREBF1/RAI1 (, )—both replicated in an independent cohort. We also replicated 20 previously discovered genetic associations (including LRRK2, GBA, SNCA, MAPT, GAK, and the HLA region), providing support for our novel study design. Relying on a recently proposed method based on genome-wide sharing estimates between distantly related individuals, we estimated the heritability of PD to be at least 0.27. Finally, using sparse regression techniques, we constructed predictive models that account for 6%–7% of the total variance in liability and that suggest the presence of true associations just beyond genome-wide significance, as confirmed through both internal and external cross-validation. These results indicate a substantial, but by no means total, contribution of genetics underlying susceptibility to both early-onset and late-onset PD, suggesting that, despite the novel associations discovered here and elsewhere, the majority of the genetic component for Parkinson's disease remains to be discovered.
We conducted a large genome-wide association study (GWAS) of Parkinson's disease (PD) with over 3,400 cases and 29,000 controls (the largest single PD GWAS cohort to date). We report two novel genetic associations and replicate a total of twenty previously described associations, showing that there are now many solid genetic factors underlying PD. We also estimate that genetic factors explain at least one-fourth of the variation in PD liability, of which currently discovered factors only explain a small fraction (6%–7%). Together, these results expand the set of genetic factors discovered to date and imply that many more associations remain to be found. Unlike traditional studies, participation in this study took place completely online, using a collection of cases recruited primarily via PD mailing lists and controls derived from the customer base of the personal genetics company 23andMe. Our study thus illustrates the ability of web-based methods for enrollment and data collection to yield new scientific insights into the etiology of disease, and it demonstrates the power and reliability of self-reported data for studying the genetics of Parkinson's disease.