Biology subjects

Taylor, K.

Publications and source records attributed to Taylor, K..

3 recordsLinked to original sources

bioRxiv2018

Prioritizing putative influential genes in early life cardiovascular disease susceptibility by applying tissue-specific Mendelian randomization

BackgroundThe extent to which changes in gene expression can influence cardiovascular disease risk across different tissue types has not yet been systematically explored. We have developed an analytical framework that integrates tissue-specific gene expression, Mendelian randomization and multiple-trait colocalization to develop functional mechanistic insight into the causal pathway from genetic variant to complex trait.\n\nMethodsWe undertook a transcriptome-wide association study in a population of young individuals to uncover genetic variants associated with both nearby gene expression and cardiovascular traits. Two-sample Mendelian randomization was then applied using large-scale datasets to investigate whether changes in gene expression within certain tissue types may influence cardiovascular trait variation. We subsequently performed Bayesian multiple-trait colocalization to further interrogate findings and also gain insight into whether DNA methylation, as well as gene expression, may play a role in disease susceptibility.\n\nResultsEight genetic loci were associated with changes in gene expression and early life measures of cardiovascular function. Our Mendelian randomization analysis provided evidence of tissue-specific effects at multiple loci, of which the effects at the ADCY3 and FADS1 loci for body mass index and cholesterol respectively were particularly insightful. Multiple trait colocalization uncovered evidence which suggested that changes in DNA methylation at the promoter region upstream of FADS1/TMEM258 may also play a role in cardiovascular trait variation along with gene expression. Furthermore, colocalization analyses were able to uncover evidence of tissue-specificity, most prominantly between SORT1 expression in liver tissue and cholesterol levels.\n\nConclusionsDisease susceptibility can be influenced by differential changes in tissue-specific gene expression and DNA methylation. Our analytical framework should prove valuable in elucidating mechanisms in disease, as well as helping prioritize putative causal genes at associated loci where multiple nearby genes may be co-regulated. Future studies which continue to uncover quantitative trait loci for molecular traits across various tissue and cell typse will further improve our capability to understand and prevent disease.

genetics↗

bioRxiv2017

Ahr and Cyp1a2 genotypes both affect susceptibility to motor deficits following gestational and lactational exposure to polychlorinated biphenyls

Polychlorinated biphenyls (PCBs) are persistent organic pollutants known to cause adverse health effects and linked to neurological deficits in both human and animal studies. Children born to exposed mothers are at highest risk of learning and memory and motor deficits. We developed a mouse model that mimics human variation in the aryl hydrocarbon receptor and cytochrome P450 1A2 (CYP1A2) to determine if genetic variation increases susceptibility to developmental PCB exposure. In our previous studies, we found that high-affinity AhrbCyp1a2(-/-) and poor-affinity AhrdCyp1a2(-/-) knockout mice were most susceptible to learning and memory deficits following developmental PCB exposure compared with AhrbCyp1a2(+/+) wild type mice (C57BL/6J strain). Our follow-up studies focused on motor deficits, because human studies have identified PCBs as a potential risk factor for Parkinsons disease. Dams were treated with an environmentally relevant PCB mixture at gestational day 10 and postnatal day 5. We used a motor battery that included tests of nigrostriatal function as well as cerebellar function, because PCBs deplete thyroid hormone, which is essential to normal cerebellar development. There was a significant effect of PCB treatment in the rotarod test with impaired performance in all three genotypes, but decreased motor learning as well in the two Cyp1a2(-/-) knockout lines. Interestingly, we found a main effect of genotype with corn oil-treated control Cyp1a2(-/-) mice performing significantly worse than Cyp1a2(+/+) wild type mice. In contrast, we found that PCB-treated high-affinity Ahrb mice were most susceptible to disruption of nigrostriatal function with the greatest deficits in AhrbCyp1a2(-/-) mice. We conclude that differences in both genes affect susceptibility to motor deficits following developmental PCB exposure.

pharmacology and toxicology↗

bioRxiv2016

Ensembl Core Software Resources: storage and programmatic access for DNA sequence and genome annotation

The Ensembl software resources are a stable infrastructure to store, access and manipulate genome assemblies and their functional annotations. The Ensembl \"Core\" database and Application Programming Interface (API) was our first major piece of software infrastructure and remains at the centre of all of our genome resources. Since its initial design more than fifteen years ago, the number of publicly available genomic, transcriptomic and proteomic datasets has grown enormously, accelerated by continuous advances in DNA sequencing technology. Initially intended to provide annotation for the reference human genome, we have extended our framework to support the genomes of all species as well as richer assembly models. Cross-referenced links to other informatics resources facilitate searching our database with a variety of popular identifiers such as UniProt and RefSeq. Our comprehensive and robust framework storing a large diversity of genome annotations in one location serves as a platform for other groups to generate and maintain their own tailored annotation. Our databases and APIs are publicly available and all of our source code is released with a permissive Apache v2.0 licence at http://github.com/Ensembl.

bioinformatics↗