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Large-effect variants in autism remain elusive. Here, the authors use long-read sequencing to assemble phased genomes for 189 individuals, identifying pathogenic variants in TBL1XR1, MECP2, and SYNGAP1, plus nine candidate structural variants missed by short-read methods.

Multi-ancestry genome-wide and transcriptome-wide association studies of aortic stenosis identify more than 200 independent risk loci and provide insights into its genetic architecture.

Pathogenic BRCA2 truncating variants in heterozygosis drive distinct cancer-linked mechanisms. Here the authors show that one causes PARPi sensitivity and HR loss via haploinsufficiency, while another expresses a truncated protein that rewires transcription by hijacking PCAF, reducing H4 acetylation and NF-κB activity.

Understanding collective behaviour is an important aspect of managing the pandemic response. Here the authors show in a large global study that participants that reported identifying more strongly with their nation reported greater engagement in public health behaviours and support for public health policies in the context of the pandemic.

Using a sample of more than 1 million individuals, Hatoum et al. identify genomic loci associated with general and substance-specific addiction risk.

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.

Different functional variants in ADH1B (and elsewhere) in Europeans and Africans strongly affect risk for alcohol dependence. Dependence only partly genetically correlates with consumption, with strong correlations to other psychiatric disorders.

Here authors reveal that placental hormone insufficiency can cause sex-linked brain inflammatory responses in mice. Altered microglial and prostaglandin signalling drive male-biased impairments, highlighting therapeutic targets for neurodevelopmental disorders.

Endocannabinoid signalling processes are implicated in body weight regulation. Here, authors used viral-genetic tools to identify the enzyme ABHD6 in postsynaptic mesoaccumbal neurons is a key determinant of body weight and reward-relevant behaviour.

Genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders identifies five underlying genomic factors that explain the majority of the genetic variance of the individual disorders.

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 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.

Our current understanding of neurofibromatosis type 1 (NF1) is based on patients ascertained through phenotype-first approaches, which estimate a low prevalence at 1 in 3,000. Here, the authors leverage a genotype-first approach in multiple large patient cohorts to demonstrate an unexpectedly high prevalence (1 in 1,286) of NF1 pathogenic variants with distinct disease associations.

Anterior Uveitis is a common inflammatory eye disease that can result in vision loss. Here, the authors perform GWAS and whole-exome analyses of Anterior Uveitis to identify the underlying genetics of HLA-B*27 positive and negative forms of the disease.

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 Stage 2 Registered Report, Buchanan et al. show evidence confirming the phenomenon of semantic priming across speakers of 19 diverse languages.

The authors find that TDP-43 loss of function—the pathology defining the neurodegenerative conditions ALS and FTD—induces novel mRNA polyadenylation events, which have different effects, including an increase in RNA stability, leading to higher protein levels.

3.4-million-year-old hominin fossils discovered in Ethiopia provide insight into the diet and locomotion of Australopithecus deyiremeda.

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).

Reduced fitness of the tumor microenvironment is mediated by a long non-coding RNA expressed in tumors.

Argonaute proteins degrade specific invader nucleic acids in eukaryotic and prokaryotic innate immunity. Here, Kanevskaya et al. describe a bacterial immune system in which RNA-guided recognition of invader DNA by Argonaute triggers formation of HNH nuclease filaments with collateral activity, protecting the bacterial population from invaders.

Here, the authors develop a self-amplifying RNA encoding the SARS-CoV-2 spike protein encapsulated within a lipid nanoparticle as a vaccine candidate and show induction of neutralization antibody titers in mice that are comparable to titers in convalescent sera of patients.

Motion vision is critical for survival. Here the authors show that motion detection occurs already in bipolar cells of the mouse retina, which may contribute to motion processing throughout the visual system.

Challenges and opportunities facing health systems have prompted a re-evaluation of long-standing assumptions about digital transformation. This editorial summarizes interviews with nurse leaders who share their perspectives on leveraging technology to drive digital transformation and improve healthcare. Key themes include smart hospitals, interoperability, and innovative care delivery methods. These insights underscore the critical role of nurse leaders in leveraging emerging technologies to enhance the care continuum and drive sustainable change.

An apparent redundant role with EZH2 has rendered EZH1 as a secondary player in PRC2-mediated homeostasis regulation. Here, the authors report that gain- and loss-of-function variants in EZH1 cause neurodevelopmental disorders, highlighting its functional relevance.

The SARS-CoV-2 protein ORF8 functions as a mimic of histone H3 to disrupt host cell epigenetic regulation.

Carriers of pathogenic BRCA1/2 variants have a higher risk of breast and ovarian cancers, which recur frequently. Here, the authors sequence primary and recurrent tumours of BRCA1/2 mutation carriers, finding PARP1 amplifications, differential BRCA2 isoform usage, and discordant loss of heterozygosity that are associated with recurrence.

Fibroblasts play critical roles in tissue homeostasis, but in pathologic states they can drive fibrosis, inflammation, and tissue destruction. Here, Faust et al. find that healthy human synovial fibroblasts under the influence of adjacent adipocytes have altered lipid metabolism driven by cortisol signaling. Both adipocytes and these characteristics are lost in inflammatory arthritis.

Placental dysfunction has been implicated in abnormal neurodevelopment. Vacher et al. found that loss of a neuroactive hormone from the placenta alters brain development in a regional and sex-linked manner, resulting in autism-like behaviors in male offspring.

The authors use integrative deconvolution of gene expression data to reveal core transcriptional features of CNS cell classes in humans, and identify cell-class-specific transcriptional differences in disease, among CNS regions, and between species.

Compact RNA structural motifs control many aspects of gene expression, but methods for their identification are lacking. Here the authors present a sequencing-based terbium probing approach to detect complex 3D structural elements, which can be used to pinpoint potential riboregulatory elements.

The circuit mechanisms underlying emotion recognition are unclear. Here, Dautan et al. show a role for a long-range feedback loop comprising somatostatin inhibitory projections from the medial prefrontal cortex (mPFC) to the retrosplenial cortex (RSC) and excitatory feedback projections from the RSC to the mPFC.

Mutations in the gene encoding Shrm4 are associated with epilepsy and intellectual disability. The authors show that Shrm4 interacts with GABA_Breceptors and regulates tonic inhibition in the hippocampus, and knockdown of Shrm4 in rats leads to anxiety-like behaviour and seizures.

Primary human hepatocyte (PHH) transplantation could be an alternative to liver transplantation. Here, the authors use the mRNA-LNP platform to express growth factors in the liver in a controlled manner to drastically improve PHH engraftment, thus, reducing disease burden and enhancing overall liver function.

Known genetic loci account for only a fraction of the genetic contribution to Alzheimer’s disease. Here, the authors have performed a large genome-wide meta-analysis comprising 409,435 individuals to discover 6 new loci and demonstrate the efficacy of an Alzheimer’s disease polygenic risk score.

The authors identified a protective genetic allele associated with lower PU.1 (SPI1) expression in myeloid cells by conducting a genome-wide scan of Alzheimer's disease (AD). PU.1 binds the promoters of AD-associated genes (e.g., CD33, MS4A4A & MS4A6A, TYROBP) and modulates their expression, suggesting it may reduce AD risk by regulating myeloid cell gene expression.

Genome-wide association analyses identify new risk loci for heart failure and its subtypes, extending understanding of the underlying biological pathways and disease mechanisms.

The rapid decay of Earth’s dipole magnetic field has recently captured the public imagination. Here, the authors present a southern hemisphere magnetic record from South African Iron Age sites using oriented samples in the floors and suggest that the anomalous field behaviour is not just a recent feature.

The demand to image large biological samples at high resolution requires improvement in current light-sheet microscopy tools. Here, the authors present an improved, benchtop mesoSPIM with a significantly increased field-of-view, improved resolution and improved throughput.

An amphiphilic mimotope vaccine can be used in tandem with Food and Drug Administration (FDA)-approved CD19 CAR-T cell products.

Encapsulation of bioactive peptides in slow-release particles is complex and relies on organic solvents. Here, the authors absorb peptides in a polymer phase from water, creating a simple low-cost encapsulation process in a class of polymer depot.

The tumor suppressor RAD51C is mutated in ovarian cancers. Through variant analysis the authors identify a mutation cluster in the RAD51C Walker B region important for the repair of DNA double-strand breaks and replicative damage. By identifying Walker B separation-of-function alleles, they show that these activities can be uncoupled.

BLINK2 is a light-activated potassium channel for optogenetic inhibition of neuronal activity. Alberio et al. apply the tool in systems as diverse as cultured rat neurons, mouse brain slices, behaving zebrafish and a rat model of neuropathic pain.