A phenome-wide association and factorial Mendelian randomization study on the repurposing of uric acid-lowering drugs for cardiovascular outcomes.

Uric acid has been linked to various disease outcomes. However, it remains unclear whether uric acid-lowering therapy could be repurposed as a treatment for conditions other than gout. We first performed both observational phenome-wide association study (Obs-PheWAS) and polygenic risk score PheWAS (PRS-PheWAS) to identify associations of uric acid levels with a wide range of disease outcomes.

Typing myalgic encephalomyelitis by infection at onset: A DecodeME study.

Background: People with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) experience core symptoms of post-exertional malaise, unrefreshing sleep, and cognitive impairment. Despite numbering 0.2-0.

Colocalization of corneal resistance factor GWAS loci with GTEx e/sQTLs highlights plausible candidate causal genes for keratoconus postnatal corneal stroma weakening.

Genome-wide association studies (GWAS) for corneal resistance factor (CRF) have identified 100s of loci and proved useful to uncover genetic determinants for keratoconus, a corneal ectasia of early-adulthood onset and common indication of corneal transplantation. In the current absence of studies to probe the impact of candidate causal variants in the cornea, we aimed to fill some of this knowledge gap by leveraging tissue-shared genetic effects. 181 CRF signals were examined for evidence of colocalization with genetic signals affecting steady-state gene transcription and splicing in adult, non-eye, tissues of the Genotype-Tissue Expression (GTEx) project.

Understanding the genetic complexity of puberty timing across the allele frequency spectrum.

Pubertal timing varies considerably and has been associated with a range of health outcomes in later life. To elucidate the underlying biological mechanisms, we performed multi-ancestry genetic analyses in ~800,000 women, identifying 1,080 independent signals associated with age at menarche. Collectively these loci explained 11% of the trait variance in an independent sample, with women at the top and bottom 1% of polygenic risk exhibiting a ~11 and ~14-fold higher risk of delayed and precocious pubertal development, respectively.

Adeno-associated virus 2 infection in children with non-A-E hepatitis.

An outbreak of acute hepatitis of unknown aetiology in children was reported in Scotland in April 2022 and has now been identified in 35 countries. Several recent studies have suggested an association with human adenovirus with this outbreak, a virus not commonly associated with hepatitis. Here we report a detailed case-control investigation and find an association between adeno-associated virus 2 (AAV2) infection and host genetics in disease susceptibility.

Rare variant analyses across multiethnic cohorts identify novel genes for refractive error.

Refractive error, measured here as mean spherical equivalent (SER), is a complex eye condition caused by both genetic and environmental factors. Individuals with strong positive or negative values of SER require spectacles or other approaches for vision correction. Common genetic risk factors have been identified by genome-wide association studies (GWAS), but a great part of the refractive error heritability is still missing.

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.

Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.

Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches.

DecodeME: community recruitment for a large genetics study of myalgic encephalomyelitis / chronic fatigue syndrome.

Background: Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) is a common, long-term condition characterised by post-exertional malaise, often with fatigue that is not significantly relieved by rest. ME/CFS has no confirmed diagnostic test or effective treatment and we lack knowledge of its causes. Identification of genes and cellular processes whose disruption adds to ME/CFS risk is a necessary first step towards development of effective therapy.