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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.

Studies on a new conditional mouse model reveal that ETS transcription factors, which are often mutated in prostate cancer, cause transformation by altering the androgen-receptor cistrome, priming the prostate epithelium to respond to upstream signals such as PTEN loss.

Inhibition of specific metabolic pathways often drives metabolic adaptation. Here, the authors show that FLT3-ITD + acute myeloid leukemia cells are OXPHOS-driven, and inhibition of complex II activity results in increased lactate influx to drive respiration, which creates a targetable vulnerability.

BMI1 and CHD7 are chromatin remodelling genes with a role in medulloblastoma pathogenesis. Here, the authors demonstrate that the BMI1^High/CHD7^Low signature mediates metabolic adaptation in G4 MB and predicts response to inositol treatment either alone or in combination with chemotherapy.

Polygenic risk scores have potential to predict an individual’s risk of disease based on genetic markers. Here, the authors develop a polygenic risk score for hypertension and test it in a multi-ethnic cohort, finding that the score is associated with higher likelihood of hypertension development 4-6 years later.

The fusion gene ZMYND11-MBTD1 (ZM) is present in a subgroup of patients with acute myeloid leukaemia (AML). Here, the authors show that ZM expression induces AML in a murine model though activating the NuA4/TIP60 histone acetyltransferase complex.

Sleep-disordered breathing (SDB) is a prevalent disorder linked to higher cardiovascular disease risk. Here, the authors show that summary scores reflecting SDB metabolite signatures are associated with increased risks for incident hypertension and diabetes, potentially useful in guiding risk stratification.

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.

Exposure to ultraviolet light is responsible for a large proportion of melanomas but the molecular mechanisms are unknown. In this study, melanoma is found to be induced in mice by UVA and UVB light in a pigment-dependent and -independent manner, respectively, resulting in different types of DNA damage.

Pérez et al. evaluate whether antibody levels and neutralization titers correlate with protection against SARS-CoV-2, including Omicron sub-variants BQ.1 and XBB, in a cohort of Spanish healthcare workers. They find an association that wanes over time, highlighting the need for updated vaccination strategies.

Increased perivascular fibroblast activity and vascular remodeling occurs early in ALS pathogenesis and can predict patient survival time

Here, the authors perform a rare-variant analysis of whole-genome sequence data that takes advantage of three global biobanks. They identify 29 novel rare variants associated with human height, and demonstrate an approach for identifying non-coding rare variants in regulatory regions with large effects from whole-genome sequencing data.

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.

Analysis of 97,691 high-coverage human blood DNA-derived whole-genome sequences enabled simultaneous identification of germline and somatic mutations that predispose individuals to clonal expansion of haematopoietic stem cells, indicating that both inherited and acquired mutations are linked to age-related cancers and coronary heart disease.

Combined hepatocellular-cholangiocarcinomas (cHCC-CCA) are challenging to diagnose, as they exhibit features of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICCA). Here, the authors use deep learning to re-classify cHCC-CCA tumours into HCC or ICCA based on histopathology images.

Brastianos and colleagues report interim trial results on the intracranial clinical benefit of palbociclib for patients with progressive metastatic brain cancer carrying cyclin-dependent kinase pathway alterations.

The influence of X chromosome genetic variation on blood lipids and coronary heart disease (CHD) is not well understood. Here, the authors analyse X chromosome sequencing data across 65,322 multi-ancestry individuals, identifying associations of the Xq23 locus with lipid changes and reduced risk of CHD and diabetes mellitus.

It is unclear how specific signalling pathways are coordinated to generate pathologically activated cancer associated fibroblasts (CAFs). Here, Ferrari et al show that stromal expression of Dickkopf-3 (DKK3) associates with aggressive tumours. DKK3 is a HSF-1 effector that activates β-catenin and YAP/TAZ, and DKK3-driven YAP/TAZ activation regulates the pro-tumorigenic behaviour of CAFs.

Many chemotherapy drugs cause sensory nerve damage as well as long-lasting damage to hematopoietic regeneration in the bone marrow. Paul Frenette and his colleagues show that this hematopoietic damage is caused by injury to bone marrow sympathetic nerve fibers, disrupting the hematopoietic stem cell niche. These findings point to the potential of neuroprotective agents in preserving hematopoietic function in chemotherapy-treated patients with cancer.

Glutaminase inhibition (GLSi) has promising activity against certain cancers. Here, the authors show that GLSi has no effect on multiple mouse models of pancreatic cancer and characterize the metabolic pathways activated in response to GLSi whose concomitant inhibition may have therapeutic utility.

The endoplasmic reticulum (ER) is a major site of lipid peroxidation during ferroptosis. Here authors show that the ER protein IRE1α determines ferroptosis induction via regulating glutathione synthesis independent of the unfolded protein response.

Branden Moriarity, David Largaespada and colleagues report a Sleeping Beauty forward genetic screen in mice that identifies candidate genes and pathways for osteosarcoma tumor development and progression. They identify sites specifically associated with tumorigenesis and metastasis and find that several candidate oncogenes are involved in axon guidance.

Timothy Frayling, Joel Hirschhorn, Peter Visscher and colleagues report a meta-analysis of genome-wide association studies for adult height in 253,288 individuals. They identify 697 variants in 423 loci significantly associated with adult height and find that these variants cluster in pathways involved in growth and together explain one-fifth of the heritability for this trait.

Analysis of antibody responses to COVID-19 vaccines encoding variant-specific spike, with or without ancestral spike, suggests no loss of neutralization of the ancestral virus with variant-only vaccines, which may simplify future vaccine updates.

Hepatitis A virus exits hepatocytes cloaked in exosomes. While the syndecan–syntenin–ALIX exosome biogenesis pathway promotes its basolateral release, human strains evolved to bypass it thus evading host antiviral pressure.

Dimethyl fumarate (DMF) is an anti-inflammatory drug proposed as a treatment for COVID19. Here the results are reported from a randomised trial testing DMF treatment in 713 patients hospitalised with COVID-19. DMF was not associated with any improvement in day 5 outcomes.

Identification of clinically relevant gene expression signatures for cancer stratification remains challenging. Here, the authors introduce a flexible nonlinear signal superposition model that enables dissection of large gene expression data sets into signatures and extraction of gene interactions.

The characterization of miR-380-5p–driven p53 repression provides a new mechanism for downmodulation of stress-induced antiproliferative responses in wild-type p53 contexts, including embryonic stem cells and neuroblastoma tumors. miR-380-5p potentiates Ras-induced mammary gland tumorigenesis and is frequently elevated in human neuroblastomas. miR-380-5p inactivation induces tumor cell death and shows therapeutic efficacy in orthotopic neuroblastoma models.

Neural stem cells have a tropism for glioblastoma. Here the authors employ fibroblasts directly reprogrammed into induced neural stem cells and loaded with cytotoxic molecules to migrate to xenotransplanted brain tumours in mice, achieving tumour shrinkage and prolonged survival.

Acidosis can stop seizures, but it is unclear how it does this. This study demonstrates that the acid-sensing channel ASIC1a is required for either spontaneous or CO₂-induced termination of convulsant-induced seizures in mice. Moreover, ASIC1a strongly activates inhibitory interneurons under acidotic conditions, which may explain the effect.

While EGFR-targeted therapies have clinical benefit, drug-resistant brain metastases present a major obstacle. Here, the authors identify a genetic signature in brain metastatic lesions associated with osimertinib resistance and find RhoA to have an important role in the resulting phenotype.

The etiology of TDP-43 proteinopathy in ALS and FTD is complex. Here, the authors show that prior to disease onset in the rNLS8 mouse model, cortex neurons elicit a transient increase in protective chaperones that combat TDP-43 aggregation.

Analysis of age of onset and disease duration in a large, international cohort of people with SOD1-ALS shows that there is a distinct phenotype and that onset and progression are decoupled.

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.

Here, the authors perform large trans-ancestry fine-mapping analyses identifying large numbers of association signals and putative target genes for colorectal cancer risk, advancing our understanding of the genetic and biological basis of this cancer.

Chen et al. report that the immune modulatory metabolite itaconic acid selectively inhibits the activity of TET DNA dioxygenases to repress the inflammatory responses.

During senescence, minority mitochondrial outer membrane permeabilization leads to the release of mtDNA into the cytosol through BAX and BAK macropores, in turn activating the cGAS–STING pathway, a major regulator of the senescence-associated secretory phenotype.

This paper describes molecular subtypes of cervical cancers, including squamous cell carcinoma and adenocarcinoma clusters defined by HPV status and molecular features, and distinct molecular pathways that are activated in cervical carcinomas caused by different somatic alterations and HPV types.

Lipid concentration in the serum is one of the most important risk factors for coronary artery disease and can be targeted for therapeutic intervention. A genome-wide association study in >100,000 individuals of European ancestry now finds 95 significantly associated loci that also affect lipid traits in non-European populations. Among associated loci are those involved in cholesterol metabolism, known targets of cholesterol-lowering drugs and those that contribute to normal variation in lipid traits and to extreme lipid phenotypes.

Longitudinal genomic and transcriptomic profiling of 1,143 patients with multiple myeloma by the Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile study yields an improved copy number and gene expression subtype scheme, most notably a high-risk proliferative subtype associated with complete loss of RB1 or MAX.