A5006613674- Genetic Associations and Epidemiology
- Genetic and phenotypic traits in livestock
- Regulation of Appetite and Obesity
- Cardiovascular Function and Risk Factors
- Lipid metabolism and disorders
- Lipoproteins and Cardiovascular Health
- Cardiovascular Disease and Adiposity
- Obesity, Physical Activity, Diet
- Asthma and respiratory diseases
- IL-33, ST2, and ILC Pathways
- Epigenetics and DNA Methylation
- Liver Disease Diagnosis and Treatment
- Cancer-related molecular mechanisms research
- Genetic Mapping and Diversity in Plants and Animals
- Lung Cancer Treatments and Mutations
- BRCA gene mutations in cancer
- Cancer Genomics and Diagnostics
- Metabolomics and Mass Spectrometry Studies
- Adipose Tissue and Metabolism
- Cancer Cells and Metastasis
University of Bristol
2020-2024
MRC Epidemiology Unit
2020
Wellcome Sanger Institute
2018
Abstract Esophageal adenocarcinoma (EAC) incidence is increasing while 5-year survival rates remain less than 15%. A lack of experimental models has hampered progress. We have generated clinically annotated EAC organoid cultures that recapitulate the morphology, genomic, and transcriptomic landscape primary tumor including point mutations, copy number alterations, mutational signatures. Karyotyping confirmed polyclonality reflecting clonal architecture tumor. Furthermore, subclones underwent...
Large-scale molecular profiling and genotyping provide a unique opportunity to systematically compare the genetically predicted effects of therapeutic targets on human metabolome. We firstly constructed genetic risk scores for 8 drug basis that they primarily modify low-density lipoprotein (LDL) cholesterol (HMGCR, PCKS9, NPC1L1), high-density (HDL) (CETP), or triglycerides (APOC3, ANGPTL3, ANGPTL4, LPL). Conducting mendelian randomisation (MR) provided strong evidence an effect drug-based...
Children with obesity typically have larger left ventricular heart dimensions during adulthood. However, whether this is due to a persistent effect of adiposity extending into adulthood challenging disentangle confounding factors throughout the lifecourse. We conducted multivariable mendelian randomization (MR) study separate independent effects childhood and adult body size on 4 magnetic resonance imaging (MRI) measures structure function in UK Biobank (UKB) study. Strong evidence...
Background: Findings from Mendelian randomization (MR) studies are conventionally interpreted as lifelong effects, which typically do not provide insight into the molecular mechanisms underlying effect of an exposure on outcome. In this study, we apply two recently developed MR approaches (known ‘lifecourse’ and ‘tissue-partitioned’ MR) to investigate lifestage-specific effects tissues action in relationship between adiposity circulating leptin levels. Methods: Genetic instruments for...
Integrating findings from genome-wide association studies with molecular datasets can develop insight into the underlying functional mechanisms responsible for trait-associated genetic variants. We have applied principles of Mendelian randomization (MR) to investigate whether brain-derived gene expression (n = 1194) may be mediating effect variants on eight cognitive and psychological outcomes (attention deficit hyperactivity disorder (ADHD), Alzheimer's disease, bipolar disorder,...
Abstract Background Body mass index (BMI) is known to influence the risk of various site-specific cancers, however, dissecting which subcomponents this heterogenous factor are predominantly responsible for driving disease effects has proven difficult establish. We have leveraged tissue-specific gene expression separate distinct phenotypes underlying BMI on seven cancers. Methods SNP-exposure estimates were weighted in a multivariable Mendelian randomisation analysis by their evidence...
Background Observational epidemiological studies have reported an association between childhood adiposity and altered cardiac morphology function in later life. However, whether this is due to a direct consequence of being overweight during has been difficult establish, particularly as accounting for other measures body composition throughout the lifecourse can be exceptionally challenging. Methods Results In study, we used human genetics investigate using causal inference technique known...
Evaluating the long-term consequences of childhood lifestyle factors on asthma risk can be exceptionally challenging in epidemiology given that cases are typically diagnosed at various timepoints throughout lifecourse. In this study, we used human genetic data to evaluate effects and adulthood adiposity pediatric (n = 13,962 cases) adult-onset 26,582 with a common set controls 300,671) using technique known as lifecourse Mendelian randomization. We found directly increases (OR 1.20, 95% CI...
Abstract Importance New drugs which provide benefit alongside statin mono-therapy are warranted to reduce risk of cardiovascular disease. Objective To systematically evaluate the genetically predicted effects 8,851 genes and disease factors using data from UK Biobank subsequently prioritize their potential in addition therapy. Design, Setting, Participants A factorial Mendelian randomization study individual level study. This population-based cohort includes a total 502,602 individuals aged...
Abstract Background Findings from Mendelian randomization (MR) studies are conventionally interpreted as lifelong effects, which typically do not provide insight into the molecular mechanisms underlying effect of an exposure on outcome. In this study, we apply two recently developed MR approaches (known ‘lifecourse’ and ‘tissue-partitioned’ MR) to investigate lifestage specific effects tissues action in relationship between adiposity circulating leptin levels. Method Genetic instruments for...
Abstract Background Separating the direct and long-term consequences of childhood lifestyle factors on asthma risk can be exceptionally challenging in epidemiology given that cases are typically diagnosed at various timepoints throughout lifecourse. Methods In this study, we used human genetic data to evaluate effects adulthood adiposity pediatric (n=13,962 cases) adult-onset (n=26,582 with a common set controls (n=300,671) using technique known as lifecourse Mendelian randomization....
Abstract Background Mendelian randomization (MR) leverages genetic variants as instrumental variables to determine causal relationships in epidemiology. However, challenges persist due heterogeneity arising from horizontal pleiotropy. On the other hand, exploration of biological underpinnings such across can enhance our understanding disease mechanisms and inform therapeutic strategies. Here, we introduce a new approach instrument partitioning based on enrichment categories compare it method...
Abstract Background Large-scale molecular profiling and genotyping provide a unique opportunity to systematically compare the genetically predicted effects of therapeutic targets on human metabolome. Methods We firstly constructed genetic risk scores for 8 drug basis that they primarily modify low-density lipoprotein (LDL) cholesterol (HMGCR, PCKS9 & NPC1L1), high-density (HDL) (CETP), or triglycerides (APOC3, ANGPTL3, ANGPTL4 LPL). then used Mendelian randomization evaluate effect each...