A two-stage meta-analysis identifies several new loci for Parkinson's Disease

A previous genome-wide association (GWA) meta-analysis of 12,386 PD cases and 21,026 controls conducted by the International Parkinson's Disease Genomics Consortium (IPDGC) discovered or confirmed 11 Parkinson's disease (PD) loci. This first analysis of the two-stage IPDGC study focused on the set of loci that passed genome-wide significance in the first stage GWA scan. However, the second stage genotyping array, the ImmunoChip, included a larger set of 1,920 SNPs selected on the basis of the GWA analysis. Here, we analyzed this set of 1,920 SNPs, and we identified five additional PD risk loci (combined p<5×10−10, PARK16/1q32, STX1B/16p11, FGF20/8p22, STBD1/4q21, and GPNMB/7p15). Two of these five loci have been suggested by previous association studies (PARK16/1q32, FGF20/8p22), and this study provides further support for these findings. Using a dataset of post-mortem brain samples assayed for gene expression (n = 399) and methylation (n = 292), we identified methylation and expression changes associated with PD risk variants in PARK16/1q32, GPNMB/7p15, and STX1B/16p11 loci, hence suggesting potential molecular mechanisms and candidate genes at these risk loci

The genetics of Parkinson's disease: Progress and therapeutic implications

The past 15 years has witnessed tremendous progress in our understanding of the genetic basis for Parkinson’s disease (PD). Notably, while most mutations, such as those in SNCA, PINK1, PARK2, PARK7, PLA2G6, FBXO7, and ATP13A2, are a rare cause of disease, one particular mutation in LRRK2, has been found to be common in certain populations. There has been considerable progress in finding risk loci. To date approximately 16 such loci exist, notably some of these overlap with the genes known to contain disease-causing mutations. The identification of risk alleles has relied mostly on the application of revolutionary technologies; likewise second generation sequencing methods have facilitated the identification of new mutations in PD. These methods will continue to provide novel insights into PD. The utility of genetics in therapeutics relies primarily on leveraging findings to understand the pathogenesis of PD. Much of the investigation into the biology underlying PD has used these findings to define a pathway, or pathways, to pathogenesis, by trying to fit disparate genetic defects onto the same network. This work has had some success, particularly in the context of monogenic disease and is beginning to provide clues about potential therapeutic targets. Approaches toward therapies are also being provided more directly by genetics; notably via the reduction and clearance of α-synuclein and inhibition of Lrrk2 kinase activity. We believe this has been an exciting and productive time for PD genetics, and furthermore, that genetics will continue to drive the etiologic understanding and etiology based therapeutic approaches in this disease