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Multi-ancestry genome-wide and transcriptome-wide association studies of aortic stenosis identify more than 200 independent risk loci and provide insights into its genetic architecture.

Oncogenic driver mutations can influence the tumour biology of lung adenocarcinomas. Here, authors analyse 157 LUAD samples using imaging mass cytometry to reveal how these mutations impact the tumour microenvironment and clinical outcomes.

Here, as part of the Sherlock-Lung study, the authors profile the microbiomes of 940 lung cancers in never smokers finding no significant associations with demographic and clinical features, suggesting lung bacteria are unlikely to have a sizable role in lung cancer.

Lung adenocarcinomas bearing the ID2 mutational signature display increased LINE-1 retrotransposon activity, which contributes to their fast evolutionary dynamics and aggressive phenotype.

Christopher Amos and colleagues perform genome-wide association analysis for lung cancer using cohorts genotyped on the OncoArray and combing these with existing data. They identify 18 loci, 10 of which are new, finding heterogeneity across the different lung cancer subtypes, and explore candidate genes through eQTL analysis in lung tissue.

Genome-wide analysis of chronic obstructive pulmonary disease identifies 82 loci, 35 of which are new. Integration of gene expression and genomic annotation data shows enrichment of signals in lung tissue, smooth muscle and several lung cell types.

The role of impaired lung function in lung cancer etiology is complex due to the relation of cigarette smoking to both conditions. Here, supported by Mendelian randomization analysis the authors find a link between pulmonary function impairment and lung cancer risk beyond smoking, implicating immune-related pathways

An analysis of data from the Sherlock-Lung study provides insight into the mutational processes that contribute to lung cancer in never smokers, and looks at the possible role of factors such as air pollution and passive smoking.

Lung cancer is the leading cause of cancer mortality, despite declining smoking rates. Gorman et al. report multi-ancestry GWAS meta-analyses of lung cancer providing insights into smoking-independent genetic predisposition to the disease.

Progressive remodeling and calcification of the aortic valve leads to calcific aortic valve stenosis (CAVS) and, ultimately, heart failure. In a combined GWAS and TWAS approach, Thériault et al. identify PALMD as a candidate causal gene for CAVS, which is further supported by Mendelian randomization.

Whole-genome sequencing of lung cancer in never smokers identifies different copy number subtypes and shows a lack of tobacco smoking signatures, even in cases exposed to secondhand smoke.

Here the authors report 20 novel genomic risk loci for calcific aortic valve stenosis, the most common heart valve disorder. Using RNA sequencing in 500 human aortic valves, they prioritize candidate causal genes including TWIST1, a gene involved in endothelial-mesenchymal transition.

A cross-ancestry genome-wide association meta-analysis of lung cancer including 61,047 cases and 947,237 controls identifies five new cross-ancestry susceptibility loci and highlights ancestry-specific effects of common and rare variants on lung cancer risk.

A genome-wide association study in more than 400,000 individuals identifies 139 new signals for lung function. These variants can predict chronic obstructive pulmonary disease in independent, transancestral cohorts.

RAS-induced senescence is a safeguarding process against tumour development. Here, the authors show that RAS activation destabilises the transcription factor ZNF768, which blocks ZNF768- dependent repression of p53 activity and thus induces senescence.

Kim Valette et al. perform a genomic study on asthma integrating genome-wide association study, functional mapping using lung and blood transcriptome-wide profiles, as well as Mendelian randomization. They show candidate causal genes expressed in lung and blood tissues that are putative therapeutic targets for asthma.

The chromosome 15q25.1 locus is a leading susceptibility region for lung cancer. Here, the authors interrogate three GWAS cohorts with 42,901 individuals to investigate potential pathological pathways such as gated channel activity and neuroactive ligand receptor interaction in lung cancer etiology.

Pulmonary function is influenced by environmental factors, lifestyle, and genetics. Here, in a multiethnic GWAS meta-analysis for pulmonary function traits, the authors identify over 50 additional genetic loci, a subset of which are specific for European, African, Asian, or Hispanic/Latino ancestry.

Genetic and environmental factors impact on lung function, important in the diagnosis of pulmonary diseases. Here the authors use imputation of genotypes to the 1000 Genomes Project reference panel to identify novel, low frequency variants associated with lung function.

Louise Wain, Ian Hall, Martin Tobin and colleagues report genome-wide association analyses of lung function, identifying 43 new signals associated with one or more lung function traits. A genetic risk score derived from these results was significantly associated with risk for chronic obstructive pulmonary disease in independent populations.

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

A single-cell atlas of the human lungs, integrating data from 2.4 million cells from 486 individuals and including samples from healthy and diseased lungs, provides a roadmap for the generation of organ-scale cell atlases.

Manikpurage et al. evaluate the association between existing polygenic risk scores (PRS) and myocardial infarction (MI) as well as the extent of coronary artery lesions at coronary angiography. The combination of several PRS could improve risk estimation of MI, extent and recurrence of atherosclerotic coronary lesions.

Michael Cho and colleagues report a genome-wide association study of risk for chronic obstructive pulmonary disease (COPD) in a large, multi-ancestry cohort. They identify 22 genome-wide significant loci, including 13 not previously associated with COPD and 4 not previously associated with any lung function trait.

Calcific aortic valve disease (CAVD) is a common disorder characterized by thickening, fibrosis and mineralization of the aortic valve leaflets. In this Review, Mathieu and colleagues summarize the risk factors, genetics and molecular mechanisms involved in CAVD and the implications for treatment of the condition.

Moncla et al. scrutinize the role of circulating proteome in mitral valve prolapse development. Integration conducted on large-scale cross-modality data uncover a causal role of the circulating proteome, immunome and macrophage M2 polarization in mitral valve prolapse.

Despite the success of human genome-wide association studies (GWAS) in associating genetic variants and complex diseases or traits, criticisms of the usefulness of this study design remain. This Review assesses the pros and cons of GWAS, with a focus on the cardiometabolic field.

Arnaud Chignon et al. present an integrated analysis of single-cell expression data from blood and genome-wide studies to identify expressed genes (eGenes) associated with human lifespan. The 125 eGenes identified are enriched for cardiometabolic traits and disorders and 16 are causally related to lifespan, as shown by Mendelian Randomization analysis.

Zhonglin Li et al. perform phenome-wide analyses to explore the genetic association between the locus near PALMD and calcific aortic valve stenosis (CAVS). Using previously reported aortic valve expression data and genotypes from large cohorts, they find a strong and specific association between genetically-determined PALMD expression in the aortic valve and CAVS as well as a novel association with atrial fibrillation in non-cardiac tissues.