Highlights d Integrated proteogenomic characterization in 103 ccRCC cases d Delineation of chromosomal translocation events leading to chromosome 3p loss d Tumor-specific proteomic/phosphoproteomic alterations unrevealed by mRNA analysis d Immune-based subtypes of ccRCC defined by mRNA, proteome, and phosphoproteome
Genes underneath signals from genome-wide association studies (GWAS) for kidney function are promising targets for functional studies, but prioritizing variants and genes is challenging. By GWAS meta-analysis for creatinine-based estimated glomerular filtration rate (eGFR) from the Chronic Kidney Disease Genetics Consortium and UK Biobank (n = 1,201,909), we expand the number of eGFRcrea loci (424 loci, 201 novel; 9.8% eGFRcrea variance explained by 634 independent signal variants). Our increased sample size in fine-mapping (n = 1,004,040, European) more than doubles the number of signals with resolved fine-mapping (99% credible sets down to 1 variant for 44 signals, ≤5 variants for 138 signals). Cystatin-based eGFR and/or blood urea nitrogen association support 348 loci (n = 460,826 and 852,678, respectively). Our customizable tool for Gene PrioritiSation reveals 23 compelling genes including mechanistic insights and enables navigation through genes and variants likely relevant for kidney function in human to help select targets for experimental follow-up.
Gene set enrichment testing can enhance the biological interpretation of ChIP-seq data. Here, we develop a method, ChIP-Enrich, for this analysis which empirically adjusts for gene locus length (the length of the gene body and its surrounding non-coding sequence). Adjustment for gene locus length is necessary because it is often positively associated with the presence of one or more peaks and because many biologically defined gene sets have an excess of genes with longer or shorter gene locus lengths. Unlike alternative methods, ChIP-Enrich can account for the wide range of gene locus length-to-peak presence relationships (observed in ENCODE ChIP-seq data sets). We show that ChIP-Enrich has a well-calibrated type I error rate using permuted ENCODE ChIP-seq data sets; in contrast, two commonly used gene set enrichment methods, Fisher's exact test and the binomial test implemented in Genomic Regions Enrichment of Annotations Tool (GREAT), can have highly inflated type I error rates and biases in ranking. We identify DNA-binding proteins, including CTCF, JunD and glucocorticoid receptor α (GRα), that show different enrichment patterns for peaks closer to versus further from transcription start sites. We also identify known and potential new biological functions of GRα. ChIP-Enrich is available as a web interface (http://chip-enrich.med.umich.edu) and Bioconductor package.
SummaryBiobanks are being established across the world to understand the genetic, environmental, and epidemiological basis of human diseases with the goal of better prevention and treatments. Genome-wide association studies (GWAS) have been very successful at mapping genomic loci for a wide range of human diseases and traits, but in general, lack appropriate representation of diverse ancestries - with most biobanks and preceding GWAS studies composed of individuals of European ancestries. Here, we introduce the Global Biobank Meta-analysis Initiative (GBMI) -- a collaborative network of 19 biobanks from 4 continents representing more than 2.1 million consented individuals with genetic data linked to electronic health records. GBMI meta-analyzes summary statistics from GWAS generated using harmonized genotypes and phenotypes from member biobanks. GBMI brings together results from GWAS analysis across 6 main ancestry groups: approximately 33,000 of African ancestry either from Africa or from admixed-ancestry diaspora (AFR), 18,000 admixed American (AMR), 31,000 Central and South Asian (CSA), 341,000 East Asian (EAS), 1.4 million European (EUR), and 1,600 Middle Eastern (MID) individuals. In this flagship project, we generated GWASs from across 14 exemplar diseases and endpoints, including both common and less prevalent diseases that were previously understudied. Using the genetic association results, we validate that GWASs conducted in biobanks worldwide can be successfully integrated despite heterogeneity in case definitions, recruitment strategies, and baseline characteristics between biobanks. We demonstrate the value of this collaborative effort to improve GWAS power for diseases, increase representation, benefit understudied diseases, and improve risk prediction while also enabling the nomination of disease genes and drug candidates by incorporating gene and protein expression data and providing insight into the underlying biology of the studied traits.
Summary
To facilitate scientific collaboration on polygenic risk scores (PRSs) research, we created an extensive PRS online repository for 35 common cancer traits integrating freely available genome-wide association studies (GWASs) summary statistics from three sources: published GWASs, the NHGRI-EBI GWAS Catalog, and UK Biobank-based GWASs. Our framework condenses these summary statistics into PRSs using various approaches such as linkage disequilibrium pruning/p value thresholding (fixed or data-adaptively optimized thresholds) and penalized, genome-wide effect size weighting. We evaluated the PRSs in two biobanks: the Michigan Genomics Initiative (MGI), a longitudinal biorepository effort at Michigan Medicine, and the population-based UK Biobank (UKB). For each PRS construct, we provide measures on predictive performance and discrimination. Besides PRS evaluation, the Cancer-PRSweb platform features construct downloads and phenome-wide PRS association study results (PRS-PheWAS) for predictive PRSs. We expect this integrated platform to accelerate PRS-related cancer research.
Background: We performed a phenome-wide association study to identify pre-existing conditions related to Coronavirus disease 2019 (COVID-19) prognosis across the medical phenome and how they vary by race. Methods: The study is comprised of 53,853 patients who were tested/diagnosed for COVID-19 between 10 March and 2 September 2020 at a large academic medical center. Results: Pre-existing conditions strongly associated with hospitalization were renal failure, pulmonary heart disease, and respiratory failure. Hematopoietic conditions were associated with intensive care unit (ICU) admission/mortality and mental disorders were associated with mortality in non-Hispanic Whites. Circulatory system and genitourinary conditions were associated with ICU admission/mortality in non-Hispanic Blacks. Conclusions: Understanding pre-existing clinical diagnoses related to COVID-19 outcomes informs the need for targeted screening to support specific vulnerable populations to improve disease prevention and healthcare delivery.
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