Browse Articles

To understand the genetic basis of disease, it is essential to study diverse populations. We conducted the largest study to date of African men to evaluate the evolutionary genetics and causes of prostate cancer. Our findings reveal novel genetic associations, including those that were not observed in studies of non-African populations.

Genome-wide association and fine-mapping analyses in approximately 260,000 Japanese individuals combined with a newly constructed Japanese-specific genotype reference panel identify hundreds of new loci and putative causal variants for 63 quantitative traits.

This study identifies context-only transcription factors (TFs), a TF class that enhances DNA accessibility initiated by cell type-specific TFs and establishes cooperative environments. Enhancers enriched with motifs of both TF classes show high coactivator binding, enhanced coordination and sensitivity to bromodomain inhibitors.

Immune recognition of cancers can be inhibited if the molecules that present cancer cell-specific antigens are disrupted. We have developed a tool that can detect four different types of disruption. Overall, we find that both genetic and non-genetic disruption of these molecules is common in lung and breast tumors.

Accurate naming of genetic variants is essential to identify clinical data that interpret the consequences of such variants. In partnership with the Human Genome Organization, we advocate for integration of VariantValidator in publishing of journals and databases, to improve the quality of shared genetic data and ultimately patient outcomes.

Genome-wide association analyses of prostate cancer in men from sub-Saharan Africa identify population-specific risk variants and regional differences in effect sizes. Founder effects contribute to continental differences in the genetic architecture of prostate cancer.

This Review discusses recurrent aneuploidies driving human cancer, methods to identify them and strategies to uncover underlying driver genes. It highlights genomic and experimental approaches to study and ultimately target driver aneuploidies.

Major histocompatibility complex (MHC) loss of heterozygosity, allele-specific mutation and measurement of expression and repression (MHC Hammer) detects disruption to human leukocyte antigens due to mutations, loss of heterogeneity, altered gene expression or alternative splicing. Applied to lung and breast cancer datasets, the tool shows that these aberrations are common across cancer and can have clinical implications.

Post-prediction genome-wide association study (POP-GWAS) is a statistical framework that uses summary statistics from labeled samples with both observed and imputed phenotypes to debias single-nucleotide polymorphism effect size estimates for unlabeled samples with imputed phenotypes only, leading to valid and powerful inference.

Large-scale multivariate analyses across populations of European ancestry identify risk loci for the metabolic syndrome, improving polygenic prediction models and highlighting associations with diverse traits beyond cardiometabolic diseases.

The mammalian inactive X chromosome shows unusual folding dominated by large-scale structures. A study finds a megadomain structure with a boundary at the Xist locus, preceding the well-known Dxz4-separated megadomains in somatic cells.

Primary cell cultures need to be frequently passaged, which limits the study of long-term biological processes, such as how mutant clones colonize aging epithelia. Esophageal epithelioids self-maintain for months, recapitulating progenitor cell behavior in vivo. Epithelioid CRISPR–Cas9 screens reveal genes encoding molecules that control cell fitness.

We identified methylated tandem repeat expansions that resemble the FMR1 CGG repeat that causes fragile X syndrome and investigated their association with traits in the UK Biobank. AFF3 expansion carriers had a 2.4-fold reduced probability of completing secondary education and were enriched in a cohort of individuals with intellectual disability.

A co-factor for the androgen receptor, NSD2, provides insights into context-specific functions of the androgen receptor and is a new target for intervention.

This study presents a spatial transcriptomic analysis of matched primary tumors, liver metastases and lymph node metastases from patients with pancreatic ductal adenocarcinoma. Using a tumor ecosystem approach, we uncovered notable tumor microenvironmental heterogeneity and marked differences between primary and metastatic samples, providing key insights into metastatic pancreatic cancer.

Somatic mutations accrue with age as patches of mutant clones arise in otherwise histologically normal tissue. The clones’ persistence, expansion and roles in physiology and tumorigenesis are unclear. New work on the behavior of Pik3caH1047R mutant esophageal clones shows that host-dependent metabolic features underpin their expansion.

Polygenic scores (PGSs) have transformed human genetic research and have numerous potential clinical applications. Here we present a series of recent enhancements to the PGS Catalog and highlight the PGS Catalog Calculator, an open-source, scalable and portable pipeline for reproducibly calculating PGSs that democratizes equitable PGS applications.

GeNA identifies cell-state abundance quantitative trait loci (csaQTLs) in single-cell RNA sequencing data. Applied to OneK1K, GeNA identifies natural killer cell and myeloid csaQTLs and implicates interferon-α-related cell states using a polygenic risk score for systemic lupus erythematosus.

Comparison of association signals in UK Biobank using different strategies for assessing genetic variation shows that whole-exome sequencing combined with array genotyping and imputation offers similar performance to whole-genome sequencing at a reduced cost.