Background Genome-wide association studies (GWASs) in Parkinson's disease (PD) have increased the scope of biological knowledge about the disease over the past decade. We sought to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into disease etiology. Methods We performed the largest meta-GWAS of PD to date, involving the analysis of 7.8M SNPs in 37.7K cases, 18.6K UK Biobank proxy-cases (having a first degree relative with PD), and 1.4M controls. We carried out a meta-analysis of this GWAS data to nominate novel loci. We then evaluated heritable risk estimates and predictive models using this data. We also utilized large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type and biological pathway enrichments for the identified risk factors. Additionally we examined shared genetic risk between PD and other phenotypes of interest via genetic correlations followed by Mendelian randomization. Findings We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16-36% of the heritable risk of PD depending on prevalence. Integrating methylation and expression data within a Mendelian randomization framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested PD loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes, smoking status, and educational attainment. Mendelian randomization between cognitive performance and PD risk showed a robust association. Interpretation These data provide the most comprehensive understanding of the genetic architecture of PD to date by revealing many additional PD risk loci, providing a biological context for these risk factors, and demonstrating that a considerable genetic component of this disease remains unidentified. Funding See supplemental materials (Text S2). lead to earlier detection and refined diagnostics, which may help improve clinical trials (4). The generation of copious amounts of public summary statistics created by this effort relating to both the GWAS and subsequent analyses of gene expression and methylation patterns may be of use to investigators planning follow-up functional studies in stem cells or other cellular screens, allowing them to prioritize targets more efficiently using our data as additional evidence. We hope our findings may have some downstream clinical impact in the future such as improved patient stratification for clinical trials and genetically informed drug targets.

SummaryResearchers worldwide with information about the Kirsten ras (Ki-ras) tumour genotype and outcome of patients with colorectal cancer were invited to provide that data in a schematized format for inclusion in a collaborative database called RASCAL (The Kirsten ras incolorectal-cancer collaborative group). Our results from 2721 such patients have been presented previously and for the first time in any common cancer, showed conclusively that different gene mutations have different impacts on outcome, even when the mutations occur at the same site on the genome. To explore the effect of Ki-ras mutations at different stages of colorectal cancer, more patients were recruited to the database, which was reanalysed when information on 4268 patients from 42 centres in 21 countries had been entered. After predetermined exclusion criteria were applied, data on 3439 patients were entered into a multivariate analysis. This found that of the 12 possible mutations on codons 12 and 13 of Kirsten ras, only one mutation on codon 12, glycine to valine, found in 8.6% of all patients, had a statistically significant impact on failure-free survival (P = 0.004, HR 1.3) and overall survival (P = 0.008, HR 1.29). This mutation appeared to have a greater impact on outcome in Dukes' C cancers (failure-free survival, P = 0.008, HR 1.5; overall survival P = 0.02, HR 1.45) than in Dukes' B tumours (failure-free survival, P = 0.46, HR 1.12; overall survival P = 0.36, HR 1.15). Ki-ras mutations may occur early in the development of pre-cancerous adenomas in the colon and rectum. However, this collaborative study suggests that not only is the presence of a codon 12 glycine to valine mutation important for cancer progression but also that it may predispose to more aggressive biological behaviour in patients with advanced colorectal cancer. © 2001 Cancer Research Campaign http://www.bjcancer.comIt is widely accepted that mutations in the Kirsten ras (Ki-ras) gene in patients with colorectal cancer develop early in the progression from adenoma to carcinoma. Our first collaborative study including 2721 patients, clarified that Ki-ras mutations are not only 692

The early human papillomavirus type 16 genes that directly participate in the in vitro transformation of primary human keratinocytes have been defined. In the context of the full viral genome, mutations in either the E6 or E7 open reading frame completely abrogated transformation of these cells. Mutations in the El, E2, and E2-E4 open reading frames, on the other hand, had no effect. Thus, both the full-length E6 and E7 genes were required for the induction of keratinocyte immortalization and resistance to terminal differentiation. The E6 and E7 genes expressed together from the human ,-actin promoter were sufficient for this transformation; mutation of either gene in the context of this recombinant plasmid eliminated the ability to induce stable differentiation-resistant transformants.

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The major transforming protein of bovine papillomavirus type 1, E5, is mainly associated with endomembranes, specifically binding to a cellular protein of relative molecular mass 16,000 (16K). At the same time as transformation, E5 causes the phosphorylation of tyrosine residues in epidermal and platelet-derived growth factor receptors. We show here that the 16K protein associated with E5 is the 16K component of vacuolar ATPases. This protein is known to be an integral membrane protein in endosomes, bovine chromaffin granules, synaptic vesicles, fungal and plant vacuoles and clathrin-coated vesicles, as well as a component of gap-junction-like membrane complexes. Because proton pumps are critical for the function of cellular compartments that process growth-factor receptors, the interaction of E5 with the 16K protein could explain the pleiomorphic features of cells transformed by E5.