Andrew Singleton, Thomas Gasser and colleagues report results of a genome-wide association study of Parkinson's disease among individuals of European ancestry. They find genome-wide significant associations at two loci, SNCA and MAPT, and provide supporting evidence for a new risk locus on 1q32. We performed a genome-wide association study (GWAS) in 1,713 individuals of European ancestry with Parkinson's disease (PD) and 3,978 controls. After replication in 3,361 cases and 4,573 controls, we observed two strong association signals, one in the gene encoding α-synuclein (SNCA; rs2736990, OR = 1.23, P = 2.24 × 10−16) and another at the MAPT locus (rs393152, OR = 0.77, P = 1.95 × 10−16). We exchanged data with colleagues performing a GWAS in Japanese PD cases. Association to PD at SNCA was replicated in the Japanese GWAS1, confirming this as a major risk locus across populations. We replicated the effect of a new locus detected in the Japanese cohort (PARK16, rs823128, OR = 0.66, P = 7.29 × 10−8) and provide supporting evidence that common variation around LRRK2 modulates risk for PD (rs1491923, OR = 1.14, P = 1.55 × 10−5). These data demonstrate an unequivocal role for common genetic variants in the etiology of typical PD and suggest population-specific genetic heterogeneity in this disease.

Mutations in the acid β-glucocerebrosidase (GBA1) gene, responsible for the lysosomal storage disorder Gaucher’s disease (GD), are the strongest genetic risk factor for Parkinson’s disease (PD) known to date. Here we generate induced pluripotent stem cells from subjects with GD and PD harbouring GBA1 mutations, and differentiate them into midbrain dopaminergic neurons followed by enrichment using fluorescence-activated cell sorting. Neurons show a reduction in glucocerebrosidase activity and protein levels, increase in glucosylceramide and α-synuclein levels as well as autophagic and lysosomal defects. Quantitative proteomic profiling reveals an increase of the neuronal calcium-binding protein 2 (NECAB2) in diseased neurons. Mutant neurons show a dysregulation of calcium homeostasis and increased vulnerability to stress responses involving elevation of cytosolic calcium. Importantly, correction of the mutations rescues such pathological phenotypes. These findings provide evidence for a link between GBA1 mutations and complex changes in the autophagic/lysosomal system and intracellular calcium homeostasis, which underlie vulnerability to neurodegeneration.

Over the past few years, genetic findings have changed our views on the molecular pathogenesis of Parkinson disease (PD), as mutations in a growing number of genes have been found to cause monogenic forms of the disorder. These mutations cause neuronal dysfunction and neurodegeneration either by a toxic gain of function, as in the case of the dominant forms of monogenic PD caused by mutations in the genes for α-synuclein or LRRK2, or by a loss of an intrinsic protective function, as is likely for the recessive PD genes parkin (PRKN), PINK1 and DJ-1. Evidence is emerging that at least some of the pathways uncovered in the rare monogenic forms of PD may play a direct role in the aetiology of the common sporadic disorder and that variants of the respective genes contribute to the risk of developing the disease. These findings will allow the search for new treatment strategies that focus on the underlying molecular pathophysiology, rather than simply on ameliorating symptoms.

Genetic variability in the promoter and 3′ region of the SNCA gene coding α‐synuclein modulates the risk to develop sporadic Parkinson's disease (PD). Whether this is mediated by regulating a‐synuclein expression levels remains unknown. Therefore, we analyzed levels of α‐synuclein in blood and human post mortem brain tissue including the substantia nigra using quantitative real‐time reverse transcriptase‐ polymerase chain reaction and enzyme linked immu‐nosorbent assay in vivo . Single nucleotide polymor‐phism (SNP) rs356219, a tagging SNP for a disease‐ associated haplotype in the 3′ region of the SNCA gene, has a significant effect on SNCA mRNA levels in the substantia nigra and the cerebellum. Further, the “protective” genotype 259/259 of the PD‐associated promoter repeat NACP‐Repl is associated with lower protein levels in blood than genotypes 261/261, 259/261, and 259/263. In conclusion, we provide evidence that a‐synuclein levels are influenced by genetic variability in the promoter and 3′ region of the SNCA gene in vivo .—Fuchs, J., Tichopad, A., Golub, Y., Munz, M., Schweitzer, K. J., Wolf, B., Berg, D., Mueller, J. C., Gasser, T. Genetic variability in the SNCA gene influences α‐synuclein levels in the blood and brain. FASEB J . 22, 1327–1334 (2008)