Publications by authors named "Andrew D Bretherick"
Choosing optimal outcome measures maximizes statistical power, accelerates discovery and improves reliability in early-phase trials. We devised and evaluated a modification to a pragmatic measure of oxygenation function, the [Formula: see text] ratio. Because of the ceiling effect in oxyhaemoglobin saturation, [Formula: see text] ratio ceases to reflect pulmonary oxygenation function at high [Formula: see text] values.
View Article and Find Full Text PDFBackground: 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.
View Article and Find Full Text PDFArticle Synopsis
- SARS-CoV-2 uses the ACE2 protein to enter human cells, making ACE2 crucial for COVID-19 infection and treatment; its levels vary significantly across different individuals but are not fully understood genetically.
- In a large study involving over 28,000 individuals, researchers found genetic factors influencing plasma ACE2 levels and discovered 10 genetic loci linked to ACE2, explaining 30% of its heritability.
- The study also indicated that higher ACE2 levels are causally associated with increased severity of COVID-19, hospitalization, and risk of infection, along with genetic links to vascular diseases and other complex health conditions.
Article Synopsis
- Critical COVID-19 is linked to immune system damage in the lungs, showing that genetics play a key role in severe cases requiring hospitalization.
- The GenOMICC study analyzes the genomes of 7,491 critically ill patients against 48,400 controls, uncovering 23 genetic variants that increase the risk for severe COVID-19, including new associations related to immune response and blood type.
- The findings suggest that both viral replication and heightened lung inflammation contribute to critically ill cases, highlighting potential genetic targets for new treatments.
Article Synopsis
- Parent-of-origin effects (POE) influence complex diseases, and it's crucial to examine how both genetic and environmental factors can modify these effects and their associated variations.
- The study screened 101 factors to assess their impact on POE regulation using data from a large Scottish health study, ultimately identifying three specific CpGs that can be modified by certain exposures.
- The findings highlight how lifestyle choices and specific gene expressions can alter DNA methylation processes, paving the way for further research into how these modifiers contribute to the understanding of complex diseases.
Background And Aims: Genome-wide association studies (GWAS) have identified several risk loci for gallstone disease. As with most polygenic traits, it is likely that many genetic determinants are undiscovered. The aim of this study was to identify genetic variants that represent new targets for gallstone research and treatment.
View Article and Find Full Text PDFGenome-wide association studies (GWAS) have identified several risk loci for nonalcoholic fatty liver disease (NAFLD). Previous studies have largely relied on small sample sizes and have assessed quantitative traits. We performed a case-control GWAS in the UK Biobank using recorded diagnosis of NAFLD based on diagnostic codes recommended in recent consensus guidelines.
View Article and Find Full Text PDFArticle Synopsis
- The study examines how genetic factors influence DNA methylation (DNAm), which is crucial for understanding gene regulation and diseases, using data from 32,851 participants.
- Researchers identified genetic variants linked to DNAm at over 420,000 sites and created a database of more than 270,000 independent mQTLs, highlighting the complexity and polygenic nature of DNAm levels.
- The findings suggest that while some shared genetic variants are linked to both DNAm and complex diseases, only a few cases indicate a direct causal relationship, revealing a complicated connection between genetics and phenotypes.
Background: The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late onset Alzheimer's disease, whilst the ε2 allele confers protection. Previous studies report differential DNA methylation of APOE between ε4 and ε2 carriers, but associations with epigenome-wide methylation have not previously been characterised.
Methods: Using the EPIC array, we investigated epigenome-wide differences in whole blood DNA methylation patterns between Alzheimer's disease-free APOE ε4 (n = 2469) and ε2 (n = 1118) carriers from the two largest single-cohort DNA methylation samples profiled to date.
Article Synopsis
- Circulating proteins play a key role in human health and are used as biomarkers for disease and drug targets; this study maps protein quantitative trait loci (pQTLs) for 90 cardiovascular proteins in over 30,000 people, discovering 451 pQTLs for 85 proteins.
- The researchers verified their findings with mouse studies and clinical trials, establishing the regulatory roles of certain genes on these proteins.
- They also identified 11 proteins with potential causal links to diseases, suggesting new drug targets and opportunities for repositioning existing drugs, thus enhancing the understanding of the genetics of proteins in relation to health.
Introduction: Dementia pathogenesis begins years before clinical symptom onset, necessitating the understanding of premorbid risk mechanisms. Here we investigated potential pathogenic mechanisms by assessing DNA methylation associations with dementia risk factors in Alzheimer's disease (AD)-free participants.
Methods: Associations between dementia risk measures (family history, AD genetic risk score [GRS], and dementia risk scores [combining lifestyle, demographic, and genetic factors]) and whole-blood DNA methylation were assessed in discovery and replication samples (n = ~400 to ~5000) from Generation Scotland.
To efficiently transform genetic associations into drug targets requires evidence that a particular gene, and its encoded protein, contribute causally to a disease. To achieve this, we employ a three-step proteome-by-phenome Mendelian Randomization (MR) approach. In step one, 154 protein quantitative trait loci (pQTLs) were identified and independently replicated.
View Article and Find Full Text PDFUnlabelled: We use a genome-wide association of 1 million parental lifespans of genotyped subjects and data on mortality risk factors to validate previously unreplicated findings near , , , , , and 13q21.31, and identify and replicate novel findings near , , and . We also validate previous findings near 5q33.
View Article and Find Full Text PDF