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cellSTAAR advances noncoding rare variant association analysis by integrating single-cell genomics data.

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.

In colorectal cancer, therapeutic resistance is driven by MAPK-dependent epithelial cell plasticity.

The Food and Drug Administration last week issued a set of regulations designed to help combat a growing scandal over drug testing in the United States. Colin Norman reports from Washington

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 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).

Italian authorities are now pondering how to clean up an area near Seveso in northern Italy, following an accident last July which released large quantities of dioxin into the environment. Some important new information bearing on the problem has surfaced in the United States. Colin Norman reports

Proteins that originate from CHO cell production systems and escape purification are of particular concern during the manufacture of therapeutic antibodies. Here, the authors show microproteins are a class of host cell protein impurity. This work facilitates improved assessment of antibody drug product quality using mass spectrometry.

MultiSTAAR provides a general and flexible statistical framework for functionally informed multi-trait rare variant analysis of biobank-scale sequencing studies by jointly analyzing multiple traits and incorporating annotation information.

A meta-analysis of genome-wide association studies of type 2 diabetes (T2D) identifies more than 600 T2D-associated loci; integrating physiological trait and single-cell chromatin accessibility data at these loci sheds light on heterogeneity within the T2D phenotype.

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

Right-sided colorectal cancer (rCRC) has a different mutational spectrum to the left-sided counterpart. Here the authors develop a mouse model of rCRC that recapitulates human BRAF-mutant rCRC and show that loss of TGFβ-receptor signalling and inflammation induce the development of colonic tumours with a foetal-like phenotype.

Using data from a single time point, passenger-approximated clonal expansion rate (PACER) estimates the fitness of common driver mutations that lead to clonal haematopoiesis and identifies TCL1A activation as a mediator of clonal expansion.

Genome-wide association and fine-mapping analyses in ancestrally diverse populations implicate candidate causal genes and mechanisms underlying type 2 diabetes. Trans-ancestry genetic risk scores enhance transferability across populations.

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.

The Tennessee Valley Authority represents an American historical landmark. Colin Norman reports

Inbreeding depression has been observed in many different species, but in humans a systematic analysis has been difficult so far. Here, analysing more than 1.3 million individuals, the authors show that a genomic inbreeding coefficient (FROH) is associated with disadvantageous outcomes in 32 out of 100 traits tested.

A multi-ancestry genome-wide gene–smoking interaction study identifies 13 new loci associated with serum lipids.

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.

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.

STAARpipeline is a comprehensive framework for flexible and scalable rare-variant association analysis using whole-genome sequencing data and annotation information.

In this immunological ancillary study of the PREVAC trial, the authors show that approved Ebola virus vaccines induce memory T-cell responses that persist during the five year follow-up after initial vaccination.

An investigation using various methods reports an association between adeno-associated virus 2 and paediatric hepatitis of unknown aetiology.

Kiourtis et al. show that liver senescence triggers senescence and dysfunction in other organs through TGFβ secretion from the liver.

Analyses of genome and exome sequencing data identify rare coding and structural variants associated with atrial fibrillation and highlight genetic links between atrial fibrillation and cardiomyopathies.

As proof of principle, an analysis using a suite of human-aligned immunocompetent mouse models of hepatocellular carcinoma identifies a promising therapeutic candidate, cladribine, which acts in a highly effective subtype-specific manner in combination with standard-of-care therapy.

Compound MMV006833 inhibits ring-stage development of Plasmodium falciparum. Here, the authors show that it targets lipid transfer enzyme PfSTART1 and prevents PfSTART1 from expanding the vacuole membrane encasing the parasite after red blood cell invasion, thereby blocking parasite growth.

Spending on science is one of the best ways to generate jobs and economic growth, say research advocates. But as Colin Macilwain reports, the evidence behind such claims is patchy.

It remains critical to identify colorectal cancers (CRC) that will disseminate as early as possible. Here, the authors identify CRC tumours that are aggressive and prone to early dissemination, characterised by epithelial TGFβ and growth-factor signalling - which could be targeted with MEK/EGFR inhibitors.

Temperatures remain high in US faculties as what started as a relatively esoteric debate on the nature of scientific knowledge continues to reverberate. Whatever their differences, both sides agree that important issues are at stake–including the role of universities themselves.

Heart failure is a complex syndrome that is associated with many different underlying risk factors. Here, to increase power, the authors jointly analyse cases of heart failure of different aetiologies in a genome-wide association study and identify 11 loci of which ten had not been previously reported.

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Dan Goldin, the administrator of the US space agency NASA, has triggered a fierce debate among physicists by suggesting that the next generation of instruments to explore the fundamental nature of matter should be built not on the ground but in space.

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.

The PSA (KLK3) genetic variant rs17632542 is associated with reduced prostate cancer risk and lower serum PSA levels, although the underlying reasons are unclear. Here, the authors show that this PSA variant reduced proteolytic activity and leads to smaller tumours, but also increases invasion and bone metastasis, indicating its dual risk association depending on tumour context; the variant is associated with both lower risk and poor clinical outcomes.

Colorectal tumors with mutated KRAS and APC require the amino acid transporter SLC7A5 to drive tumorigenesis. Mechanistically, SLC7A5 drives transcriptional and metabolic reprogramming by maintaining intracellular amino acid levels, leading to enhanced protein synthesis.