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Variants in the PSMC5 gene impair proteasome function and cellular homeostasis, altering brain development in children. This study reveals underlying molecular mechanisms contributing to this neurodevelopmental phenotype, and suggests therapeutic leads for neurodevelopmental proteasomopathies.

Here, using metagenomics, the authors show that the gut microbiome of rural Zimbabwean infants undergoes programmed maturation that is unresponsive to sanitation and nutrition interventions but is strongly associated with maternal HIV infection and can moderately predict linear growth.

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.

This study reveals that an outer membrane protein from the predator Bdellovibrio bacteriovorus forms a pentameric assembly that traps a lipid monolayer within. This allows the discovery of two superfamilies, distributed across a wide range of bacteria, likely to adopt a similar architecture.

Whole-genome sequencing, transcriptome-wide association and fine-mapping analyses in over 7,000 individuals with critical COVID-19 are used to identify 16 independent variants that are associated with severe illness in COVID-19.

The authors identify pathogenic variants in the SMARCA1 gene as the cause of a variable neurodevelopmental disorder. Mouse studies suggest diverse genetic mechanisms related to NURF complex composition mediate the phenotype.

Fine-mapping of causal variants and integration of epigenetic and chromatin conformation data identify likely target genes for 150 breast cancer risk regions.

Polygenic scores for body mass index and obesity constructed using data from 5 million people with different ancestries were associated with distinct weight gain trajectories from early childhood to adulthood.

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.

A large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants.

Meta-analysis of genome-wide association studies on Alzheimer’s disease and related dementias identifies new loci and enables generation of a new genetic risk score associated with the risk of future Alzheimer’s disease and dementia.

Therapeutic options for patients with renal medullary carcinoma (RMC) are limited. Here the authors report the results of a phase II clinical trial of anti-PD1 nivolumab plus anti-CTLA4 ipilimumab in RMC, associating the activation of a myeloid mimicry program in tumor cells to the rapid disease progression and hyper-progression observed in treated patients.

Here the authors apply machine learning approaches to Alzheimer’s genetics, confirm known associations and suggest novel risk loci. These methods demonstrate predictive power comparable to traditional approaches, while also offering potential new insights beyond standard genetic analyses.

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.

Terrestrial ecosystem productivity is widely accepted to be nutrient limited. A series of standardized nutrient addition experiments, carried out on grasslands on five continents, suggests aboveground grassland productivity is commonly limited by multiple nutrients, including potassium and micronutrients.

Microglial states throughout remyelination are incompletely understood. Here, the authors show that microglia form several states during the early stages of remyelination that coalesce into a partially resolved state that is dysregulated with age.

Rebecca and colleagues discuss the complex biology of metastatic melanoma, as well as determinants of resistance to therapy and existing and promising therapy strategies.

Known genetic loci account for only a fraction of the genetic contribution to Alzheimer’s disease. Here, the authors have performed a large genome-wide meta-analysis comprising 409,435 individuals to discover 6 new loci and demonstrate the efficacy of an Alzheimer’s disease polygenic risk score.

Polygenic risk scores for Alzheimer’s disease derived from individuals of European ancestry can show improved performance in multiancestry settings after incorporating genome-wide association summary statistics from diverse populations.

In this Review, Grapsa and colleagues provide an overview of the imaging modalities used in the diagnosis and management of tricuspid regurgitation, describe the valve repair and replacement strategies undergoing clinical testing, and highlight the technological innovations that aim to optimize diagnosis, patient selection and the device development process.

In this Q&A, we speak to US Congresswoman Judy Chu (D-CA), who has served as the representative for the 28th congressional district of California since 2009. In addition to being a member of the House Ways and Means Committee, she has also been a member of the Subcommittees on Health, Worker and Family Support, and Oversight that oversee legislation pertaining to health programs, healthcare reform, and research.

Large genome-wide meta-analysis of clinically diagnosed late-onset Alzheimer’s disease (LOAD) from 94,437 individuals identifies new LOAD risk loci and implicates Aβ formation, tau protein binding, immune response and lipid metabolism.

To consider the impact of sex on adaptation to space, the European Space Agency initiated VIVALDI dry immersion microgravity simulation in female subjects. Here, the authors show marked deconditioning with 5-day exposure, and propose comprehensive multi-system physiological assessment in 18 healthy women.

White matter hyperintensities are linked to cortical atrophy, a key feature in dementia. Here, the authors identify loci associated with cortical atrophy related to white matter hyperintensities, which involve vascular and neuronal processes.

Here the authors identify 33 individuals with a dominant neurodevelopmental disorder due to heterozygous missense or loss-of-function variants in the gene encoding Densin-180, a scaffold protein present at postsynaptic sites in neurons of the central nervous system.

An investigation using various methods reports an association between adeno-associated virus 2 and paediatric hepatitis of unknown aetiology.

In this Stage 2 Registered Report, Buchanan et al. show evidence confirming the phenomenon of semantic priming across speakers of 19 diverse languages.

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.

Authors show that base editing can convert sickle hemoglobin (HbS) to the rare but naturally occurring variant G-Makassar (HbG). Purified HbG appears normal, but in a mouse model, HbGS red cells sickle under hypoxia, highlighting the importance of assessing red cell quality when evaluating novel gene editing strategies for hematologic disorders.

Multiancestry genome-wide association analyses identify new risk loci for stroke and stroke subtypes. Fine mapping and bioinformatics analyses of these risk loci point to mechanisms not previously implicated in stroke pathophysiology.

Similarities in cancers can be studied to interrogate their etiology. Here, the authors use genome-wide association study summary statistics from six cancer types based on 296,215 cases and 301,319 controls of European ancestry, showing that solid tumours arising from different tissues share a degree of common germline genetic basis.

Data from over 700,000 individuals reveal the identity of 83 sequence variants that affect human height, implicating new candidate genes and pathways as being involved in growth.

This work integrates duplex sequencing with cost-effective Ultima sequencing to enhance the accuracy of whole-genome circulating cell-free DNA profiling.

A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.

Leveraging four large, longitudinal, prospectively-followed mother–child cohorts, this study shows that a western diet in early–mid-pregnancy is associated with neurodevelopmental disorders in the offspring.

The Cancer Genome Atlas reports on molecular evaluation of 295 primary gastric adenocarcinomas and proposes a new classification of gastric cancers into 4 subtypes, which should help with clinical assessment and trials of targeted therapies.

Genome-wide association analyses identify new risk loci for heart failure and its subtypes, extending understanding of the underlying biological pathways and disease mechanisms.

Multi-ancestry meta-analyses of genome-wide association studies for self-reported physical activity during leisure time, leisure screen time, sedentary commuting and sedentary behavior at work identify 99 loci associated with at least one of these traits.

Missense variants in RNA-binding proteins underlie many diseases. Here the authors report an oculopharyngeal muscular dystrophy caused by heterozygous frameshift mutations in HNRNPA2B1 that alter its nucleocytoplasmic transport dynamics and result in cytoplasmic accumulation of hnRNPA2 protein.

An antibody screen of two distinct multiple sclerosis cohorts reveals an autoantibody signature that is detectable years before symptom onset and linked to a common microbial motif.

Nematode signals such as ascarosides are sensed by G protein-coupled receptors of a nematode-trapping fungus, resulting in fungal activation of cAMP–PKA signalling and trap development.