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Here the authors show how the DNA-sensing cGAS–STING pathway activates NF-κB and inflammatory gene expression with delayed kinetics via post-Golgi endolysosomal signaling.

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 genome-wide association meta-analysis study of blood lipid levels in roughly 1.6 million individuals demonstrates the gain of power attained when diverse ancestries are included to improve fine-mapping and polygenic score generation, with gains in locus discovery related to sample size.

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.

Gut microbial metabolism of nutrients contributes to metabolic diseases, and the histidine metabolite imidazole propionate (ImP) is produced by type 2 diabetes (T2D) associated microbiome. Here the authors report that circulating ImP levels are increased in subjects with prediabetes or T2D in three European populations, and this increase associates with altered gut microbiota rather than dietary histidine.

Clinical multi-omics data are integrated and analyzed using a generative deep-learning model.

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.

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.

There are currently only a few biomarkers to predict the response of muscle invasive bladder cancer to therapy. Here, the authors analyse 300 tumors using exome and RNA sequencing and find that tumors with a high degree of genomic instability and a non-basal/squamous gene expression subtype are most likely to respond to treatment.

TMAO is known to be atherothrombotic. Here the authors show that i) kidney function is the main determinant of serum TMAO, ii) TMAO increases kidney scarring with TGF-β1 signalling and iii) anti-diabetic drugs with reno-protective properties such as GLP1R agonists reduce plasma TMAO.

Thyroid dysfunction is involved in many diseases. Here, the authors provide insights into the genetics and biological pathways influencing important thyroid function parameters, showing potential causal effects on many clinical outcomes.

PAQR4 regulates cellular ceramide synthesis and accumulation to mediate adipose tissue function, glucose homoeostasis and, thus, systemic metabolic health.

The details of how the protein folding and degradation systems collaborate to combat potentially toxic non-native proteins are unknown. Here the authors perform systematic studies of missense and nonsense variants of the cytosolic aspartoacylase, ASPA, where loss-of-function variants are linked to Canavan disease.

The levels of 1,251 metabolites are measured in 475 phenotyped individuals, and machine-learning algorithms reveal that diet and the microbiome are the determinants with the strongest predictive power for the levels of these metabolites.

Genome-wide analyses using fetal and parental genotypes identify 40 independent associations influencing placental weight and highlight the role of the fetus in preeclampsia risk and placental growth regulation via insulin signaling.

Transmembrane signaling is the core adaptation in nature that allows cells to communicate. Here, the authors engineer signaling through the lipid bilayer using chemical, synthetic receptors for their use in the design of artificial cells.

Many genetic variants have been associated with human traits, but the mechanism is often unknown. Here, the authors integrate local and distal genetic associations with multi-omics datasets to provide a roadmap to understand the underlying mechanisms of GWAS variants on complex traits.

Obesity is linked to cancer risk in post-menopausal breast cancer. At the molecular level this is governed by cellular adaption to palmitic acid through epigenetic activation of a C/EBPB-dependent transcriptional network that drives tumor formation.

Maternal genome-wide analyses identify variants associated with gestational duration and preterm delivery. Maternal alleles positively associated with gestational duration exhibit negative fetal effects on birth weight, likely reflecting antagonistic pleiotropy.

In people with HIV-1 undergoing antiretroviral treatment interruption, lefitolimod combined with broadly neutralizing antibodies (bNAbs) did not delay viral rebound beyond that achieved with bNAbs alone, raising the question of how to optimize combination immunotherapy to control HIV-1.

Paul Pharoah and colleagues report the results of a large genome-wide association study of ovarian cancer. They identify new susceptibility loci for different epithelial ovarian cancer histotypes and use integrated analyses of genes and regulatory features at each locus to predict candidate susceptibility genes, including OBFC1.

Oxaliplatin resistance in colorectal cancers is a major clinical problem, and predictive markers are urgently needed. Here, the authors show that miR-625-3pexpression reduces the sensitivity of colorectal cancer cells to oxaliplatin by targeting the kinase MAP2K6, an activator of the MAPK14 pathway.

Insulin resistance and lower muscle strength in relation to mass are hallmarks of type 2 diabetes. Here, the authors report alterations in muscle stem cells from individuals with type 2 diabetes that may contribute to these phenotypes through VPS39 mediated effects on autophagy and epigenetics.

This study uses gene expression predictors for the dorsolateral prefrontal cortex and other brain regions to perform a transcriptomic imputation analysis of schizophrenia, identifying 413 genic associations across 13 brain regions and 36 significantly enriched pathways.

Here the authors generate a capsid-like particle based vaccine candidate displaying the receptor-binding domain of the SARS-CoV-2 spike protein and show induction of neutralizing antibodies after intramuscular prime-boost immunization in mice.

Trans-ethnic analyses of exome array data identify new risk loci for type 2 diabetes. Fine-mapping analyses using genome-wide association data show that the index coding variants represent the likely causal variants at only a subset of these loci.

Establishing the relative transmissibility of emerging variants of SARS-CoV-2 is key for pandemic management. Here, the authors use full-population administrative data from Denmark linked to PCR test results and estimate that the Alpha variant was ~60% higher than other strains circulating in early 2021.

This Review highlights the interindividual and intraindividual variability of TSH levels and discusses the current controversy that surrounds the appropriateness of reference ranges defined on the basis of age, race, sex and amount of iodine intake. Moreover, the current evidence on lowering or increasing the upper limit of the TSH reference interval is reviewed and the need to individualize levothyroxine treatment in patients with elevated TSH levels is discussed.