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Genome-wide association analyses of 41,917 bipolar disorder cases and 371,549 controls of European ancestry provide new insights into the etiology of this disorder and identify novel therapeutic leads and potential opportunities for drug repurposing.

PDZ domains facilitate numerous protein-binding interactions, and their prevalence in the human genome has led to their investigation as drug targets. Here, the authors generate semisynthetic PDZ domains containing backbone mutations for the identification of important ligand-binding interactions.

Relatively little is known about the mechanisms that underlie the active transport of ions by Na⁺,K⁺-ATPase. A 3.5 Å X-ray structure of this fundamental protein is presented, revealing the two binding sites for potassium.

This study uncovered genetic associations with environmental sensitivity in psychiatric and neurodevelopmental traits in an international collaboration using data from more than 21,000 monozygotic twins—the largest genetic study of monozygotic twin differences to date.

Integrative analyses of transcriptome and whole-genome sequencing data for 1,188 tumours across 27 types of cancer are used to provide a comprehensive catalogue of RNA-level alterations in cancer.

Two polypeptides synthesized by common bacterial strains in human gut microbiota lower body fat and blood glucose and increase bone density, improving the metabolism of rodents.

Sequencing the microbial species present in complex metagenomic samples is made easier with a method that groups genes by co-abundance.

Gamma-ray bursts (GRBs) are known to have impact on Earth’s lower ionosphere, but GRB impacts on the upper ionosphere was not observed before. Here, the authors show strong electric field variation at 500 km in the ionosphere caused by GRB221009A.

Using multi-ancestry genome-wide association study and fine-mapping, 298 loci and 36 credible genes are identified in the aetiology of bipolar disorder.

With the generation of large pan-cancer whole-exome and whole-genome sequencing projects, a question remains about how comparable these datasets are. Here, using The Cancer Genome Atlas samples analysed as part of the Pan-Cancer Analysis of Whole Genomes project, the authors explore the concordance of mutations called by whole exome sequencing and whole genome sequencing techniques.

An analysis involving the shotgun sequencing of more than 300 ancient genomes from Eurasia reveals a deep east–west genetic divide from the Black Sea to the Baltic, and provides insight into the distinct effects of the Neolithic transition on either side of this boundary.

In this study the authors consider the structural variants (SVs) present within cancer cases of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. They report hundreds of genes, including known cancer-associated genes for which the nearby presence of a SV breakpoint is associated with altered expression.

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.

DeepRETStroke is a deep learning system using retinal photographs to detect silent brain infarction and predict future stroke events.

A genome-wide study by the Long COVID Host Genetics Initiative identifies an association between the FOXP4 locus and long COVID, implicating altered lung function in its pathophysiology.

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.

Genome-wide association analyses comprising 14,256 cases and 1,199,156 controls and incorporating correlated cardiac magnetic resonance imaging traits provide insights into the molecular etiology of dilated cardiomyopathy.

Phosphorus mononitride is highly unstable under atmospheric conditions and its utility for constructing elusive P–N π-bonded motifs has remained uncertain. Here, the authors show that Na(OCP) can transfer a P atom to an electrophilic osmium nitride complex to form a metal-bound P≡N ligand.

Meta-analyses in up to 1.3 million individuals identify 87 rare-variant associations with blood pressure traits. On average, rare variants exhibit effects ~8 times larger than the mean effects of common variants and implicate candidate causal genes at associated regions.

Narcolepsy has genetic and environmental risk factors, but the specific genetic risk loci and interaction with environmental triggers are not well understood. Here, the authors identify genetic loci for narcolepsy, suggesting infection as a trigger and dendritic and helper T cell involvement.

Genetic variants discovered through genome-wide association studies for asthma together account for a small portion of the heritability. Here, the authors identify a possible epistatic relationship between coding variants in FUT2 and ABO, especially pronounced in severe and early onset asthma.

A meta-analysis of genome-wide association studies of type 2 diabetes (T2D) identifies more than 600 T2D-associated loci; integrating physiological trait and single-cell chromatin accessibility data at these loci sheds light on heterogeneity within the T2D phenotype.

The antidepressant vortioxetine affects rodent and human 5-HT₃ receptors differently. López-Sánchez et al. use a variety of methods, including structure determination of vortioxetine-bound human and mouse 5-HT₃ receptors, to reveal the basis of these differences.

Rats and mice have a thermoneutral point below which metabolic rate rises and above which body temperature rises and heat stress occurs, with rats overheating more easily; housing temperatures of 28–29 °C best minimize both cold stress and overheating

Primary ovarian insufficiency (POI) is a clinical syndrome of ovarian dysfunction that results in infertility. Here they show that BCN1 mutation results in premature ovarian follicle activation and atresia through dysregulation of ferroptosis.

By studying individuals along a spectrum of cardiometabolic disease and adjusting for effects of lifestyle and medication, this investigation identifies alterations of the metabolome and microbiome from dysmetabolic conditions, such as obesity and type 2 diabetes, to ischemic heart disease.

Integration of GWAS and single-cell transcriptomic data from the entire nervous system systematically identifies cell types underlying brain complex traits and provides insights into the etiology of Parkinson’s disease.

The misfolding of alpha-synuclein is associated with neurodegenerative disorders such as Parkinson’s disease. The authors report a mechanism explaining why lipid membranes catalyze the formation of harmful aggregates at elevated concentrations.

An analysis of 2,173 individuals from the MetaCardis cohort quantifies the individual and combinatorial effects of a range of drugs on host health, metabolome and gut microbiome in cardiometabolic disease.

Women worry that their IBD will flare during pregnancy. A prospective multicentre study from Europe has now demonstrated that although women with Crohn's disease do not have an increased risk of relapse during pregnancy, women with ulcerative colitis are at increased risk of relapse, both during pregnancy and postpartum.

Increased potential for branched-chain amino acid and lipopolysaccharide biosynthesis in the gut microbiome of insulin-resistant individuals suggests that changes in the serum metabolome induced by dysbiosis, and driven by only a handful of species, contribute to the development of diabetes.

A cross-sectional analysis of participants in the MetaCardis Body Mass Index Spectrum cohort finds that the higher prevalence of gut microbiota dysbiosis in individuals with obesity is not observed in those who take statin drugs.