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The authors in this work identify an in vivo CNS active bifunctional degrader of GSK3. This was discovered via development of orthogonally reactive linker chemistry and a direct-to-biology screen that was able to provide hits of in vivo chemical probe quality.

To better understand the etiology of frailty, the authors perform a large genetic study. They identified 45 additional variants and implicated MET, CHST9, ILRUN, APOE, CGREF1 and PPP6C as potential causal genes, linking frailty to immune regulation, metabolism and cellular signaling.

The authors present results from the REACT-2 study, a series of cross-sectional community surveys during the SARS-CoV-2 pandemic in England. They measure antibodies by self-administered lateral flow tests and describe antibody positivity by time since vaccination, age, sex, co-morbidities, infection history, and vaccine type.

Genome-wide association studies of individuals from an isolated population (data from the Finnish biobank study FinnGen) and consequent meta-analyses facilitate the identification of previously unknown coding variant associations for both rare and common diseases.

This study presents data from the REACT-1 SARS-CoV-2 community sampling study in England from November 2021 to March 2022. They show that the Omicron variant peaked in January with a prevalence of ~7% and that the BA.2 sublineage had a 1.5x higher reproduction number compared to other Omicron sublineages.

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).

Obesity has been reported to promote tumourigenesis and chemoresistance but the underlying mechanisms are not completely understood. Here, the authors show that adipocytes induce Galectin-9 (GAL-9) expression in B-acute lymphoblastic leukaemia (B-ALL) cells which leads to chemoresistance and antibody-mediated blockade of GAL-9 increases survival in preclinical B-ALL murine models.

This manuscript evaluates forecasts of laboratory-confirmed influenza hospital admissions, a new target for influenza forecasting in the United States. Across two influenza seasons, the FluSight ensemble is robust compared to submitted models.

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.

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.

A genome-wide association study identifies 17 genetic loci that are associated with the risk of myeloproliferative neoplasms (MPNs), and shows that the modulation of haematopoietic stem cell function drives MPN risk.

Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide and genetic susceptibility to the disease is poorly understood. Here, the authors combine data from Japanese, African American and European samples and identify a common variant in VTI1Athat increases CRC risk across all populations.

Previous studies have shown that both rare pathogenic mutations and common genetic variants contribute to the familial risk of developing colorectal cancer. Here, the authors carry out a two-stage genome-wide association study and identify six new loci associated with colorectal cancer.

This study characterises Long COVID using data from the REACT-2 community-based study in England. It estimates that 38% (in autumn/winter 2020/21) and 22% (in spring 2021) of people reported at least one symptom 12 weeks after symptom onset; identifies risk factors for persistent symptoms; and finds evidence of symptom clustering.

Wei Zheng and colleagues report the results of a large-scale genome-wide association study of colorectal cancer in East Asians. They identify six new susceptibility loci, including variants near TCF7L2 and TGFB1.

Tendinopathy, although common, is difficult to treat, and most currently available treatments are not effective or evidence-based. As outlined in this Review, the molecular pathology of the tendon is being elucidated and could lead to the identification of novel therapeutic agents for the treatment of chronic tendinopathies.

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.

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.

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.

A genome-wide association study suggests 41 previously unreported loci on top of the 23 known loci that influence the disease risk for lumbar disc herniations. Many of these loci harbour genes implicated in disc structure and inflammation, as well as genes related to the nervous system and nerve function.

Many genetic factors that contribute to uterine leiomyomata (UL) - the most common tumours of the female genital tract - remain to be discovered. Here, the authors conduct a UL meta-genome-wide association study, and find loci related to altered muscle tissue biology that are associated with UL.

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.

The value of SARS-CoV-2 lateral flow immunoassay tests for estimating individual disease risk is unclear. Here, the authors link testing data from the REACT-2 study in England to hospital and death records and show that vaccinated individuals with a negative LFIA test were at a higher risk of hospitalisation and death.

REACT-2 is a large-scale community study of SARS-CoV-2 seroprevalence in England. Here, the authors estimate that 6% of adults in England had been infected by mid-July 2020, with health and long-term care workers and those of Black or South Asian ethnicity disproportionately affected.

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.

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.

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.

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.

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.

Identifying women at high risk of breast cancer has important implications for screening. Here, the authors demonstrate that polygenic risk scores improve breast cancer risk prediction in the population, in women with mutations in high-risk genes and in women with close relatives with the disease.

Cardiovascular diseases (CVD) are associated with plasma lipid levels. Here, Tabassum et al. perform genome-wide association studies for lipidomic profiles with 141 (non-standard) lipid species which highlights shared genetic loci with CVD and that traditional lipids have low genetic correlation with other lipids.

Prostate cancer often does not progress to invasive disease and thus markers predicting the course of the disease progression are critical for optimal treatment choices. Here the authors show that variants at two genetic loci correlate with the aggressiveness of prostate cancer.

William Dobyns and colleagues report de novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA in the sporadic overgrowth syndromes megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) and megalencephaly-capillary malformation (MCAP).

In a large and prospective cohort, higher polygenic risk is associated with higher risk and earlier age of onset for cardiometabolic disorders and cancer, and has added value to clinical risk scores in clinical disease prediction.

Wei Zheng and colleagues report genome-wide analyses in east Asians and identify three new loci associated with colorectal cancer risk.