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The global burden of Metabolic syndrome is incompletely characterized. Here the authors report a systematic review and modelling study showing that global metabolic syndrome prevalence doubled from 2000 to 2023, now affecting 1.54 billion adults (31.0% of women, 25.7% of men), with higher rates in women, urban areas, and high-income countries, with disparities across regions.

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

Analysis of samples from the asteroid Ryugu provide evidence of late fluid flow in a carbonaceous asteroid, indicating that such bodies may have retained two to three times more water than previously thought.

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.

Inborn errors of the alternative NF-κB pathway in humans impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases

Here the authors use a range of approaches to examine the interplay between genetic variants linked to risk for polygenic skin diseases and transcription factors (TFs) important for skin homeostasis. The findings implicate dysregulated binding of specific TF families in risk for diverse skin diseases.

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.

A region on chromosome 19p13 is associated with the risk of developing ovarian and breast cancer. Here, the authors genotyped SNPs in this region in thousands of breast and ovarian cancer patients and identified SNPs associated with three genes, which were analysed with functional studies.

This report by the Consortium for Refractive Error and Myopia uses gene-environment-wide interaction study (GEWIS) to identify genetic loci that affect environmental influence in myopia development, and identifies ethnic specific genetic loci that attribute to eye refractive errors.

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).

Low read depth sequencing of whole genomes and high read depth exomes of nearly 10,000 extensively phenotyped individuals are combined to help characterize novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with lipid-related traits; in addition to describing population structure and providing functional annotation of rare and low-frequency variants the authors use the data to estimate the benefits of sequencing for association studies.

PepMLM designs peptide binders against diverse targets using masked language modeling.

Sexual dimorphism in genetic vulnerability to schizophrenia, systemic lupus erythematosus and Sjögren’s syndrome is linked to differential protein abundance from alleles of complement component 4.

Derailed differentiation of human-specific progenitors of the developing cerebellar rhombic lip is the cause of group 4 medulloblastoma, the most common childhood brain tumour. 

Analysis of 4,041 single-nucleotide variants (SNVs) linked to 13 cancers performed in primary human cell types identifies 380 potentially regulatory SNVs and their putative target genes. Editing one SNV, rs10411210, revealed that the risk allele increases RHPN2 expression and stimulus-responsive RhoA activation.

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.

Some quantum acoustic resonators possess a large number of phonon modes at different frequencies. Direct interactions between modes similar to those available for photonic devices have now been demonstrated. This enables manipulation of multimode states.

Association analysis identifies 65 new breast cancer risk loci, predicts target genes for known risk loci and demonstrates a strong overlap with somatic driver genes in breast tumours.

Here the authors show that BTLA on effector T cells interacts with HVEM on other immunosuppressive cells in the tumor microenvironment. The authors also present evidence that overcoming this checkpoint can ehance CAR T functionality.

Primary open-angle glaucoma (POAG) is highly heritable, yet not well understood from a genetic perspective. Here, the authors perform a meta-analysis of genome-wide association studies in 34,179 POAG cases, identifying 44 previously unreported risk loci and mapping effects across multiple ethnicities.

Epigenomic profiling and massively parallel reporter assays identify 892 functional differentially-active single-nucleotide variants (daSNVs) linked to ten neuropsychiatric diseases. CRISPRi and gene editing approaches show magnesium transport dysfunction as a common genetic pathomechanism.

Roger Milne and colleagues conduct a genome-wide association study for estrogen receptor (ER)-negative breast cancer combined with BRCA1 mutation carriers in a large cohort. They identify ten new risk variants and find high genetic correlation between breast cancer risk for BRCA1 mutation carriers and risk of ER-negative breast cancer in the general population.

The original Cancer Cell Line Encyclopedia (CCLE) is expanded with deeper characterization of over 1,000 cell lines, including genomic, transcriptomic, and proteomic data, and integration with drug-sensitivity and gene-dependency data.

Brain–machine interfaces using steady-state visually evoked potentials (SSVEPs) show promise in therapeutic applications. With a combination of innovations in flexible and soft electronics and in deep learning approaches to classify potentials from two channels and from any subject, a compact, wireless and universal SSVEP interface is designed. Subjects can operate a wheelchair in real time with eye movements while wearing the new brain–machine interface.

In Drosophila, the Calypso–ASX complex catalyzes H2A deubiquitination and aids Polycomb in transcriptional silencing. Here the authors show that the orthologous complex, BAP1.com, promotes gene activation by counteracting PRC1-mediated gene silencing.

Neutralizing nanobodies (Nb) are of considerable interest as therapeutic agents for COVID-19 treatment. Here, the authors functionally and structurally characterize Nbs that bind with high affinity to the receptor binding domain of the SARS-CoV-2 spike protein and show that an engineered homotrimeric Nb prevents disease progression in a Syrian hamster model of COVID-19 when administered intranasally.

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.

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.

A variety of signals have been reported to either activate or inhibit the Hippo kinase cascade. Here, Meng et al. show that mitogen activated protein kinase kinase kinase kinase (MAP4K) family members function in parallel to and are partially redundant with MST1/2 in regulating LATS in response to upstream signals.

The burden of mosaic chromosomal alterations in blood-derived DNA, a type of clonal hematopoiesis, is associated with an increased risk for diverse types of infections, including sepsis and pneumonia.

Levels of circulating thyrotropin and free thyroxine reflect thyroid function, however, their genetic underpinnings remain poorly understood. Taylor et al. take advantage of whole-genome sequence data from cohorts within the UK10K project to identify novel variants associated with these traits.

Chemical modification of PS-ASO therapeutics reduces binding to cellular proteins and decreases toxic side-effects.

The response to infectious and inflammatory challenges differs among people but the reasons for this are poorly understood. Here the authors explore the impact of variables such as age, sex, and the capacity for controlling inflammation and maintaining immunocompetence, linking this capacity to favourable health outcomes and lifespan.

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.

Enhancer variants associated with red blood cell traits alter signaling transcription factor motifs, leading to changes in expression of genes that are upregulated during erythroid differentiation.

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.

Size and shape of the brain are, among others, influenced by the dimensions of the skull. Here, the authors report genome-wide association studies for head circumference and intracranial volume in children and adults and the identification of nine common or low-frequency variants associated with these traits.

This study describes the integrative analysis of 111 reference human epigenomes, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression; the results annotate candidate regulatory elements in diverse tissues and cell types, their candidate regulators, and the set of human traits for which they show genetic variant enrichment, providing a resource for interpreting the molecular basis of human disease.

Imputation uses genotype information from SNP arrays to infer the genotypes of missing markers. Here, the authors show that an imputation reference panel derived from whole-genome sequencing of 3,781 samples from the UK10K project improves the imputation accuracy and coverage of low frequency variants compared to existing methods.

Population-based genome sequencing provides an increasingly rich resource for the identification of low-frequency, large effect variants associated with clinically important phenotypes. Timpson et al. use UK10K data to identify a variant of the APOC3gene strongly associated with plasma triglyceride levels.

Results for the final phase of the 1000 Genomes Project are presented including whole-genome sequencing, targeted exome sequencing, and genotyping on high-density SNP arrays for 2,504 individuals across 26 populations, providing a global reference data set to support biomedical genetics.

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.

Patrick Sullivan and colleagues report a multi-stage genome-wide association study for schizophrenia in a Swedish population. They identify 13 loci newly associated with schizophrenia.