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<5x10(-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

Author Correction: Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Emmanuelle Souzeau, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this Article. This has now been corrected in both the PDF and HTML versions of the Article

Targeted therapies: how personal should we go?

Despite the development of drugs inhibiting the oncogenic proteins that cancer cells are dependent on, attempts to match targeted therapies to the genetic makeup of individual tumors is proving more difficult than expected. Until now, the paradigm has been a binary correlation between a mutated cancer gene and response to a given therapy. However, recent evidence indicates that different genetic alterations, such as mutations in different codons of a cancer gene, might be related to distinct sensitivity to targeted therapies. An example is the divergent effect that individual EGFR, PIK3CA and KRAS mutations might have on response or resistance to tailored drugs. Furthermore, the idea that the presence of a specific mutation translates into sensitivity or resistance to a particular drug is likely too simplistic, since it does not capture the complexity of the signaling pathways in an individual cancer. Only the overall genetic milieu (alterations in upstream and/or parallel pathways) ultimately determines the response of individual tumors to therapy. We have critically analyzed data supporting the genetic, biological and biochemical differences of individual mutations within a single cancer gene. The role of cancer mutations as predictors of sensitivity and resistance to targeted therapies is discussed, together with the implications for the 'personalized' treatment of cancer patients

Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies

Item does not contain fulltextBACKGROUND: Genome-wide association studies (GWAS) for Parkinson's disease have linked two loci (MAPT and SNCA) to risk of Parkinson's disease. We aimed to identify novel risk loci for Parkinson's disease. METHODS: We did a meta-analysis of datasets from five Parkinson's disease GWAS from the USA and Europe to identify loci associated with Parkinson's disease (discovery phase). We then did replication analyses of significantly associated loci in an independent sample series. Estimates of population-attributable risk were calculated from estimates from the discovery and replication phases combined, and risk-profile estimates for loci identified in the discovery phase were calculated. FINDINGS: The discovery phase consisted of 5333 case and 12 019 control samples, with genotyped and imputed data at 7 689 524 SNPs. The replication phase consisted of 7053 case and 9007 control samples. We identified 11 loci that surpassed the threshold for genome-wide significance (p<5x10(-8)). Six were previously identified loci (MAPT, SNCA, HLA-DRB5, BST1, GAK and LRRK2) and five were newly identified loci (ACMSD, STK39, MCCC1/LAMP3, SYT11, and CCDC62/HIP1R). The combined population-attributable risk was 60.3% (95% CI 43.7-69.3). In the risk-profile analysis, the odds ratio in the highest quintile of disease risk was 2.51 (95% CI 2.23-2.83) compared with 1.00 in the lowest quintile of disease risk. INTERPRETATION: These data provide an insight into the genetics of Parkinson's disease and the molecular cause of the disease and could provide future targets for therapies. FUNDING: Wellcome Trust, National Institute on Aging, and US Department of Defense