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In triple-negative breast cancer, the kinase PIM1, which is highly expressed, functions through the transcription factor c-MYC to promote tumor cell survival and growth.

Brown adipose tissue activation of thermogenesis is accompanied by a sequence of events commonly associated with apoptosis, however they evade cell death. Assali et al. show that NCLX prevents mitochondrial calcium overload and apoptosis. Deletion of NCLX, converts a thermogenic signal into a death pathway.

Multi-omics datasets pose major challenges to data interpretation and hypothesis generation owing to their high-dimensional molecular profiles. Here, the authors develop ActivePathways method, which uses data fusion techniques for integrative pathway analysis of multi-omics data and candidate gene discovery.

Chronic care manages long-term, progressive conditions, while acute care handles short-term ones. Here, authors show chronic conditions account for most of the global health burden, with 68% of DALYs and 93% of YLDs attributed to chronic care needs.

The variability in clinical outcomes of SARS-CoV-2 infection is partly due to deficiencies in production or response to type I interferons (IFN). Here, the authors describe a FIP200-dependent lysosomal degradation pathway, independent of canonical autophagy and type I IFN, that restricts SARS-CoV-2 replication, offering insights into critical COVID-19 pneumonia mechanisms.

The advantage of living in cities compared with rural areas with respect to height and BMI in children and adolescents has generally become smaller globally from 1990 to 2020, except in sub-Saharan Africa.

Intestinal homeostasis is maintained by interactions between the gut-associated lymphoid tissue and the resident flora. Here Montorsi et al use multiplexed single cell omics to describe double negative type 2 B cells and DNASE1L3-expressing dendritic cells that interact and associate with microbiota on the human gut antigenic front line.

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.

Analyses of 2,658 whole genomes across 38 types of cancer identify the contribution of non-coding point mutations and structural variants to driving cancer.

An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

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.

Integrated multi-omic analyses using samples from the TRACERx study highlight cross-talk between DNA hypermethylation and genomic lesions in non-small cell lung cancer.

The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 cancer whole genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.

Exercise training decreases pancreatic islet senescence through glucagon and AMPK signalling in mouse and human islets, which could have implications for T2DM therapeutics.

A genome-wide association study of critically ill patients with COVID-19 identifies genetic signals that relate to important host antiviral defence mechanisms and mediators of inflammatory organ damage that may be targeted by repurposing drug treatments.

Viral pathogen load in cancer genomes is estimated through analysis of sequencing data from 2,656 tumors across 35 cancer types using multiple pathogen-detection pipelines, identifying viruses in 382 genomic and 68 transcriptome datasets.

An analysis of 2,954 genomes from 38 cancer subtypes identified 19,166 retrotransposition events in 35% of samples. Aberrant LINE-1 retrotranspositions can lead to the deletion of tumor-suppressor genes as well as the amplification of oncogenes.

Comparison of non-invasive [¹¹C]metomidate PET-CT with adrenal vein sampling for predicting biochemical remission of primary aldosteronism showed non-superiority, suggesting that the non-invasive method is suitable for the diagnosis of unilateral primary aldosteronism.

Here authors show that machine learning derives the degree of background retinal pigmentation with more nuance than self-described ethnicity. Retinal pigment scores are associated with genes linked to melanin and may improve algorithmic fairness.

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.

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.

Psoriasis is a partially heritable skin disorder, the genetic basis of which is not fully understood. Here, the authors use genome-wide association meta-analysis to discover psoriasis susceptibility loci and genes, which encode existing and potential new drug targets.

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.

Mammalian genomes are scattered with repetitive sequences, but their biology remains largely elusive. Here, the authors show that transcription can initiate from short tandem repetitive sequences, and that genetic variants linked to human diseases are preferentially found at repeats with high transcription initiation level.

The characterization of 4,645 whole-genome and 19,184 exome sequences, covering most types of cancer, identifies 81 single-base substitution, doublet-base substitution and small-insertion-and-deletion mutational signatures, providing a systematic overview of the mutational processes that contribute to cancer development.

In this study, the authors provide a global overview of SARS-CoV-2 genome sequencing, and estimate the proportion of cases sequenced and time to genome upload. They identify disparities and highlight the need to strengthen surveillance in lower and middle income countries.

Sera from vaccinated individuals and some monoclonal antibodies show a modest reduction in neutralizing activity against the B.1.1.7 variant of SARS-CoV-2; but the E484K substitution leads to a considerable loss of neutralizing activity.

Swanton and colleagues present a clonal expression signature, ORACLE, which, in combination with clinicopathological and molecular risk factors, can predict survival of patients with lung adenocarcinoma, and they prospectively validate its prognostic value.

Vaccination is effective in protecting from COVID-19. Here the authors report immune responses and breakthrough infections in twice-vaccinated patients receiving anti-TNF treatments for inflammatory bowel disease, and find dampened vaccine responses that implicate the need of adapted vaccination schedules for these patients.

Analysing camera-trap data of 163 mammal species before and after the onset of COVID-19 lockdowns, the authors show that responses to human activity are dependent on the degree to which the landscape is modified by humans, with carnivores being especially sensitive.

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.

Patient-derived xenografts are important tools for cancer drug development. Here, the authors develop models from 22 non-small cell lung cancer patients. They show genomic differences between models created from different spatial regions of tumours and a bottleneck on model establishment.

Pancreatic β-cells are highly connected, and this network is crucial for the pulsatile release of insulin. Here Salem and colleagues demonstrated the existence of leader β-cells that respond first to glucose and are more closely linked to the other β-cells. They also showed that glucose increases β-cell calcium dynamics and connectivity between the leader and non-leader β-cells.

A study of the evolution of the SARS-CoV-2 virus in England between September 2020 and June 2021 finds that interventions capable of containing previous variants were insufficient to stop the more transmissible Alpha and Delta variants.

Whole-genome sequencing and phenotype data sharing are introduced in a national health system to streamline diagnosis and to discover coding and non-coding variants that cause rare diseases.

Exponential growth of toxigenic Streptococcus pyogenes M1_UK lineage accounted for most of the 2022/2023 invasive infection upsurge in the UK. Authors provide evidence that M1_UK first emerged in 2008, has genetic evidence of enhanced fitness, and has disseminated to 3 continents.

Mixed responses to targeted therapy within a patient are a clinical challenge. Here the authors show that TP53 loss-of-function cooperates with whole genome doubling which increases chromosomal instability. This leads to greater cellular diversity and multiple routes of resistance, which in turn promotes mixed responses to treatment.

Major histocompatibility complex (MHC) loss of heterozygosity, allele-specific mutation and measurement of expression and repression (MHC Hammer) detects disruption to human leukocyte antigens due to mutations, loss of heterogeneity, altered gene expression or alternative splicing. Applied to lung and breast cancer datasets, the tool shows that these aberrations are common across cancer and can have clinical implications.

Immune lymphocyte estimation from nucleotide sequencing (ImmuneLENS) infers B cell and T cell fractions from whole-genome sequencing data. Applied to the 100,000 Genomes Project datasets, circulating T cell fraction provides sex-dependent and prognostic insights in patients.

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.

From 1980 to 2018, the levels of total and non-high-density lipoprotein cholesterol increased in low- and middle-income countries, especially in east and southeast Asia, and decreased in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe.

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.

Combination of epidemiology, preclinical models and ultradeep DNA profiling of clinical cohorts unpicks the inflammatory mechanism by which air pollution promotes lung cancer

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.

Julie Lessard and colleagues report that ATP-dependent SWI/SNF chromatin-remodeling complex subunit SMARCD2 is essential for granulocyte development. They find that Smarcd2-deficient mice fail to generate functioning neutrophils and eosinophils, and they determine that the divergent coiled-coil 1 and SWIB domains are responsible for functional specificity during granulocyte differentiation.

A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology.