Web-based genome-wide association study identifies two novel loci and a substantial genetic component for Parkinson's disease

Abstract

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 (p = 7.6 × 10(-10), OR = 0.84) and rs11868035 near SREBF1/RAI1 (p = 5.6 × 10(-8), OR = 0.85)-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.

Figure 1. Plot of -values around rs6812193 and SCARB2.

In the plot, circles represent unannotated SNPs, upside-down triangles represent non-synonymous variants, and boxes with an “x” are SNPs in regions that are highly conserved across 44 placental mammals. Colors depict the squared correlation () of each SNP with the most associated SNP (i.e., rs6812193). Purple designates the SNP with the strongest association, and gray indicates SNPs for which information was missing. Plots were produced using the LocusZoom program .

Figure 2. Plot of -values around rs11868035 and SREBF1/RAI1.

Colors depict the squared correlation () of each SNP with rs11868035. For details, see Figure 1.