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Progression of chronic kidney disease may lead to kidney failure and cardiovascular, metabolic and bone disease complications. Here, the authors conduct a large-scale proteomic study in patients with chronic kidney disease, identify numerous proteins that predict kidney failure, some of which are likely causal mediators and hence potential therapeutic targets.

How the mitochondrial electron transport chain (ETC) interacts with the NLRP3 inflammasome is somewhat unclear. Here the authors use individual complex inhibitors and new genetic models to show that ETC is critical in providing ATP via the phosphocreatine shuttle to activate the NLRP3 inflammasome.

Vitamin D deficiency is associated with multiple human pathologic conditions. In a genome-wide association study of 79,366 individuals, Jiang et al. replicate four and identify two new genetic loci for serum levels of 25-hydroxyvitamin D and find evidence for a shared genetic basis with autoimmune diseases.

The emergence of resistant Plasmodiumstrains fuels the search for new antimalarials. Here, the authors present a new class of potent antimalarial compounds, the triaminopyrimidines, that display low toxicity and long half-life in animal models.

Genome-wide association analyses identify variants associated with thoracic aortic diameter. A polygenic score for ascending aortic diameter was associated with a diagnosis of thoracic aortic aneurysm in independent samples.

Most studies of the genetics of the metabolome have been done in individuals of European descent. Here, the authors integrate genomics and metabolomics in Black individuals, highlighting the value of whole genome sequencing in diverse populations and linking circulating metabolites to human disease.

Daniel Chasman, Daniel Levy, Christopher Newton-Cheh, Georg Ehret and colleagues perform an association meta-analysis for blood pressure in ∼330,000 individuals and identify 31 new risk loci, implicating biological pathways related to vascular function and cardiometabolic traits. Their findings highlight potential therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk.

Several GWAS have identified many common variants associated with blood metabolites. Here, the authors use an exome array to identify low frequency, potentially functional variants that impact human metabolism.

Coronary artery calcium is an accurate predictor of cardiovascular events but this information is not routinely quantified. Here the authors show a robust and time-efficient deep learning system to automatically quantify coronary calcium on CT scans and predict cardiovascular events in a large, multicentre study.

Chronic obstructive pulmonary disease is a leading cause of morbidity and mortality. Here, the authors analyse whole genome sequence data and find new loci associated with lung function and COPD.

Metabolomic profiling provides clues at alterations in cellular biochemistry. Here, the authors perform metabolomics analyses on samples from the Framingham Heart Study, and a Danish validation cohort, to identify small-molecule biomarkers prospectively associated with longevity or ageing.

Krebs and colleagues identify multiple mAbs that recognize either the RBD or the NTD of SARS-CoV-2 spike protein that have potent cross-neutralizing activities against variants of concern. Combinatorial mAb cocktails have complementary effects on viral neutralization and Fc effector functions and can protect against SARS-CoV-2 escape mutants.

Daniel Levy and colleagues report a meta-analysis of genome-wide association studies for blood pressure traits as part of the CHARGE consortium, reporting eight loci with replicated association to systolic and/or diastolic blood pressure, with one of these loci also associated to hypertension.

Reduced glomerular filtration rate (eGFR) is a hallmark of chronic kidney disease. Here, Pattaro et al. conduct a meta-analysis to discover several new loci associated with variation in eGFR and find that genes associated with eGFR loci often encode proteins potentially related to kidney development.

Common genetic variants associated with plasma lipids have been extensively studied for a better understanding of common diseases. Here, the authors use whole-genome sequencing of 16,324 individuals to analyze rare variant associations and to determine their monogenic and polygenic contribution to lipid traits.

Clonal hematopoiesis of indeterminate potential (CHIP) was found to be associated with a protective effect from Alzheimer’s disease (AD) in large population-based cohorts.

Platelet aggregation is associated with myocardial infarction and stroke. Here, the authors have conducted a whole genome sequencing association study on platelet aggregation, discovering a locus in RGS18, where enhancer assays suggest an effect on activity of haematopoeitic lineage transcription factors.

Oxidation of ubiquinol by the mitochondrial electron transfer chain drives tumour growth by maintaining the function of the oxidative Krebs cycle and de novo pyrimidine synthesis.

Here, the authors perform a whole-genome sequencing association analysis of genetic variants in ≤11,840 multi-ethnic participants with ≤1666 circulating metabolites, discovering 1985 novel variant-metabolite associations and insights into human disease.

Composite mutations, of two or more nonsynonymous somatic mutations in the same cancer-associated gene, are present in nearly one in four human tumours.

Pooling participant-level genetic data into a single analysis can result in variance stratification, reducing statistical performance. Here, the authors develop variant-specific inflation factors to assess variance stratification and apply this to pooled individual-level data from whole genome sequencing.

HIV-1 Env consensus sequences that reflect recent sequences for clades B, C, and CRF01_AE were redesigned using AI-assisted methods to shorten hypervariable loops and limit strain-specific targeting. The modified Envs show improved antibody binding.

SARS-CoV-2 variants of concern continue to emerge, reducing vaccine efficacy and limiting therapeutic options. Here, Chen and colleagues describe the identification and design of shark nanobodies with pansarbecovirus activity.

Genetic and genomic approaches — including high-throughput sequence analysis and transcriptomics experiments — are revealing a clearer picture of the pathophysiological steps underlying the different forms of heart failure (genetic and acquired) and the genomic responses to cardiac overload.

Christopher Newton-Cheh and colleagues report the identification of common variants at the NPPA-NPPB locus associated with plasma atrial natriuretic peptide concentration, as well as with lower systolic and diastolic blood pressure, and reduced risk of hypertension.

Most genetic association studies have been done on single nucleotide polymorphisms and small indels, while other types of variants have been less studied. Here, the authors use whole genome sequencing in a diverse population to identify and provide experimental evidence for associations between structural variants and blood-cell traits.

Amino acid profiles could aid in diabetes risk assessment, as a five-amino-acid signature had highly significant associations with the development of future diabetes in two large, independent cohorts.

Chandarlapaty and colleagues use longitudinal ctDNA samples to identify genomic alterations in PTEN and ESR1 associated with resistance in a phase I/II trial of a PI3K inhibitor and aromatase inhibition for hormone receptor–positive metastatic breast cancer.

Missegregated chromosomes that are sequestrated in micronuclei are subject to changes in histone modifications leading to abnormalities in chromatin accessibility that remain long after the chromosomes have been reincorporated into the primary nucleus.

de Vries, Conomos, Singh and Nicholson et al. identify two additional loci associated with coronary artery calcification (ARSE and MMP16) via a genome-wide association study in 22,400 participants from multiple ancestral groups and prove that ARSE is a mediator of vascular smooth muscle cell calcification and phenotype switching.

Novak, Lin et al. use AI computational drug prediction and CRISPR-enabled in vivo disease modeling to identify therapeutic strategies for the treatment of Rett syndrome. Findings reveal the therapeutic efficacy of vorinostat in a mouse model of Rett syndrome.

Paul Elliott, Martin Tobin, Cornelia van Duijn and colleagues report a genome-wide association study for pulse pressure and mean arterial pressure, identifying six new loci influencing these two traits.

The Framingham Heart Study (FHS) has been collecting epidemiological data on cardiovascular risk factors and disease for >70 years. In this Timeline Perspectives article, the authors summarize the major achievements of the FHS, highlight some of the seminal publications and discuss how epidemiological research has changed and continues to evolve.

Patrick Ellinor and colleagues report a genome-wide association study identifying variants in KCNN3 associated to lone atrial fibrillation.