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The goals, resources and design of the NHLBI Trans-Omics for Precision Medicine (TOPMed) programme are described, and analyses of rare variants detected in the first 53,831 samples provide insights into mutational processes and recent human evolutionary history.

Here the authors reveal a two-step spatiotemporal regulation of (Polθ)-mediated end-joining (TMEJ). First, PARP1 PARylates Polθ and facilitates its recruitment to the vicinity of DNA damage sites in an inactivated state. PARG subsequently activates TMEJ by removing repressive PAR marks on Polθ.

Primary biliary cirrhosis is an autoimmune liver disease with poor therapeutic options. Here Cordell et al. a perform meta-analysis of European genome-wide association studies identifying six novel risk loci and a number of potential therapeutic pathways.

Chronic infection with SARS-CoV-2 leads to the emergence of viral variants that show reduced susceptibility to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma.

The genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher genetically predicted RHR decreases risk of atrial fibrillation and ischemic stroke.

A genomic constraint map for the human genome constructed using data from 76,156 human genomes from the Genome Aggregation Database shows that non-coding constrained regions are enriched for regulatory elements and variants associated with complex diseases and traits.

A cross-ancestry meta-analysis of genome-wide association studies identifies association signals for stroke and its subtypes at 89 (61 new) independent loci, reveals putative causal genes, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as potential drug targets, and provides cross-ancestry integrative risk prediction.

GWAS have identified more than 500 genetic loci associated with blood lipid levels. Here, the authors report a genome-wide analysis of interactions between genetic markers and physical activity, and find that physical activity modifies the effects of four genetic loci on HDL or LDL cholesterol.

A multi-ancestry transcriptome-wide association study using an optimal linear combination of association statistics provides insights into tobacco use biology and suggests opportunities for drug repurposing.

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.

This overview of the ENCODE project outlines the data accumulated so far, revealing that 80% of the human genome now has at least one biochemical function assigned to it; the newly identified functional elements should aid the interpretation of results of genome-wide association studies, as many correspond to sites of association with human disease.

STAARpipeline is a comprehensive framework for flexible and scalable rare-variant association analysis using whole-genome sequencing data and annotation information.

FRESH, a multi-lab collaboration, reveals how data quality, analysis pipelines, and researcher expertise influence reproducibility in fNIRS neuroimaging, highlighting key factors driving variability in hypothesis outcomes.

B cell–mediated inhibition of T cell trafficking is impaired in inflammatory disease.

Drugs targeting cardiovascular disease (CVD) can have negative consequences for liver function. Here, the authors combine genome wide analyses on 69,479 individuals to identify loss-of-function variants with beneficial effects on CVD-related traits without negative impacts on liver function.

In this study, Aggarwal and colleagues perform prospective sequencing of SARS-CoV-2 isolates derived from asymptomatic student screening and symptomatic testing of students and staff at the University of Cambridge. They identify important factors that contributed to within university transmission and onward spread into the wider community.

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.

Although the common genetic variants contributing to blood lipid levels have been studied, the contribution of rare variants is less understood. Here, the authors perform a rare coding and noncoding variant association study of blood lipid levels using whole genome sequencing data.

Native chemical ligation (NCL) has revolutionized the field of chemical protein synthesis. This Review discusses milestones such as desulfurization, the development of thiol and selenol analogues of proteinogenic amino acids and novel acyl donors for multi-component iterative ligations. These have greatly expanded the NCL concept and enabled the synthesis of hitherto inaccessible protein targets.

Cognitive function is associated with health and important life outcomes. Here, the authors perform a genome-wide association study for general cognitive function in 300,486 individuals and identify genetic loci that implicate neural and cell developmental pathways in this trait.

Heart failure is a complex syndrome that is associated with many different underlying risk factors. Here, to increase power, the authors jointly analyse cases of heart failure of different aetiologies in a genome-wide association study and identify 11 loci of which ten had not been previously reported.

The authors defined a roadmap for investigating the genetic covariance between structural or functional brain phenotypes and risk for psychiatric disorders. Their proof-of-concept study using the largest available common variant data sets for schizophrenia and volumes of several (mainly subcortical) brain structures did not find evidence of genetic overlap.

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.

Analysis of whole-genome sequences of 25,465 individuals of European ancestry shows that rare variants contribute substantially to the heritability of height and body mass index.

Openshaw and colleagues find myeloid inflammation and complement activation signatures in patients with long COVID who were previously hospitalized.

John Perry and colleagues report the results of a large genome-wide association study meta-analysis to identify variants influencing age at natural menopause. They identify 54 independent signals and find enrichment near genes involved in delayed puberty and DNA damage response.

A strategy for inferring phase for rare variant pairs is applied to exome sequencing data for 125,748 individuals from the Genome Aggregation Database (gnomAD). This resource will aid interpretation of rare co-occurring variants in the context of recessive disease.

Samples of different body regions from hundreds of human donors are used to study how genetic variation influences gene expression levels in 44 disease-relevant tissues.

This study presents an extensive molecular characterization of the reprograming process by analysis of transcriptomic, epigenomic and proteomic data sets describing the routes to pluripotency; it finds distinct routes towards two stable pluripotent states characterized by distinct epigenetic events.

Postsurgical adhesions are a problem during routine cardiothoracic procedures. Here, the authors report on a catechol functionalised hydrogel as an anti-adhesion material with improved retention on the heart which is biocompatible and biodegradable with minimal swelling, demonstrating application in vivo.

A study shows that clonal haematopoiesis of indeterminate potential is associated with an increased risk of chronic liver disease specifically through the promotion of liver inflammation and injury.

The future challenges and potential opportunities of robotics and autonomous systems in urban ecosystems, and how they may impact biodiversity, are explored and prioritized via a global horizon scan of 170 experts.

Most Amazon tree species are rare but a small proportion are common across the region. The authors show that different species are hyperdominant in different size classes and that hyperdominance is more phylogenetically restricted for larger canopy trees than for smaller understory ones.

Genome-wide association studies have only revealed a handful of genetic loci for longevity. Here, in a case–control design based on phenotype definitions of individuals surviving at or beyond the age corresponding to the 90th and 99th survival percentile, the authors report two additional loci located in the APOE locus and near GPR78.

Holistic indicator frameworks are needed to track food systems transformation. This Analysis shows the application of a framework recently developed by the Food Systems Countdown Initiative to all UN member states, revealing current status, data gaps and priority actions.

Post-international travel quarantine has been widely implemented to mitigate SARS-CoV-2 transmission, but the impacts of such policies are unclear. Here, the authors used linked genomic and contact tracing data to assess the impacts of a 14-day quarantine on return to England in summer 2020.

A randomized trial in patients hospitalized with COVID-19 showed no benefit and potentially increased harm associated with the use of convalescent plasma, with subgroup analyses suggesting that the antibody profile in donor plasma is critical in determining clinical outcomes.

Heart rate variability (HRV) describes the individual variation in cardiac cycle duration and is a measure of vagal control of heart rate. Here, the authors identify seventeen single-nucleotide polymorphisms associated with HRV, lending new insight into the vagal regulation of heart rhythm.

Phenotypic variation and diseases are influenced by factors such as genetic variants and gene expression. Here, Barbeira et al. develop S-PrediXcan to compute PrediXcan results using summary data, and investigate the effects of gene expression variation on human phenotypes in 44 GTEx tissues and >100 phenotypes.

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.

Daniel Benjamin, Meike Bartels, Philipp Koellinger and colleagues report a genome-wide association meta-analysis of subjective well-being, depressive symptoms and neuroticism. The study leverages a large sample size together with genetic correlations between the phenotypes to identify, with high confidence, loci associated with each phenotype.

Anthropology can offer valuable insights into the science, impacts and policy of climate change thanks to its fieldwork methodology, holistic view of society and engagement in society–environment interactions. Yet the discipline's voice in climate change debates remains marginal. This Perspective sheds light on how anthropological research can contribute to the understanding of climate change.

An analysis of 16 health-related quantitative traits in approximately 350,000 individuals reveals statistically significant associations between genome-wide homozygosity and four complex traits (height, lung function, cognitive ability and educational attainment); in each case increased homozygosity associates with a decreased trait value, but no evidence was seen of an influence on blood pressure, cholesterol, or ten other cardio-metabolic traits.

Using the GTEx data and others, a comprehensive analysis of adenosine-to-inosine RNA editing in mammals is presented; targets of the various ADAR enzymes are identified, as are several potential regulators of editing, such as AIMP2.