Biology subjects

Paul, D. S.

Publications and source records attributed to Paul, D. S..

7 recordsLinked to original sources

bioRxiv2018

Interleukin-6 Receptor Signalling and Abdominal Aortic Aneurysm Growth Rates

BackgroundThe Asp358Ala variant (rs2228145; A>C) in the interleukin-6 receptor (IL6R) gene has been implicated in the development of abdominal aortic aneurysms (AAAs), but its effect on AAA growth over time is not known. We aimed to investigate the clinical association between the IL6R-Asp358Ala variant and AAA growth, and to assess the effect of blocking the IL-6 signalling pathway in mouse models of aneurysm rupture.\n\nMethodUsing data from 2,863 participants with AAA from nine prospective cohorts, age- and sex-adjusted mixed-effects linear regression models were used to estimate the association between the IL6R-Asp358Ala variant and annual change in AAA diameter (mm/year). In a series of complementary randomised trials in mice, the effect of blocking the IL-6 signalling pathways was assessed on plasma biomarkers, systolic blood pressure, aneurysm diameter and time to aortic rupture and death.\n\nResultsAfter adjusting for age and sex, baseline aneurysm size was 0.55mm (95% confidence interval [CI]: 0.13, 0.98mm) smaller per copy of the minor allele [C] of the Asp358Ala variant. There was no evidence of a reduction in AAA growth rate (change in growth=-0.06mm per year [-0.18, 0.06] per copy of the minor allele). In two mouse models of AAA, selective blockage of the IL-6 trans-signalling pathway, but not combined blockage of both, the classical and trans-signalling pathways, was associated with improved survival (p<0.05).\n\nConclusionsOur proof-of-principle data are compatible with the concept that IL-6 trans-signalling is relevant to AAA growth, encouraging larger-scale evaluation of this hypothesis.

genetics↗

bioRxiv2018

Genetic effects on promoter usage are highly context-specific and contribute to complex traits

Genetic variants regulating RNA splicing and transcript usage have been implicated in both common and rare diseases. Although transcript usage quantitative trait loci (tuQTLs) have now been mapped in multiple cell types and conditions, the molecular mechanisms through which these variants exert their effect have remained elusive. Specifically, changes in transcript usage could arise from promoter choice, alternative splicing or 3' end choice, but current tuQTL studies have not been able to distinguish between them. Here, we performed comprehensive analysis of RNA-seq data from human macrophages exposed to a range of inflammatory stimuli (IFN{gamma}, Salmonella, IFN{gamma} + Salmonella) and a metabolic stimulus (acetylated LDL), obtained from up to 84 individuals. In addition to conventional gene-level and transcript-level analyses, we also developed an analytical approach to directly quantify promoter, internal exon and 3' end usage. We found that although naive transcript-level analysis often links single genetic variants to multiple coupled changes on the transcriptome, this appears to be an artefact of incomplete transcript annotations. Most of this coupling disappears when promoters, splicing and 3' end usage are quantified directly. Furthermore, promoter, splicing and 3' end QTLs are each enriched in distinct genomic features, suggesting that they are predominantly controlled by independent regulatory mechanisms. We also find that promoter usage QTLs are 50% more likely to be context-specific than canonical splicing QTLs and constitute 25% of the transcript-level colocalisations with complex traits. Thus, promoter usage might be a previously underappreciated molecular mechanism mediating complex trait associations in a context-specific manner.

genomics↗

bioRxiv2018

Selfish mutations dysregulating RAS-MAPK signaling are pervasive in aged human testes

Mosaic mutations present in the germline have important implications for reproductive risk and disease transmission. We previously demonstrated a phenomenon occurring in the male germline, whereby specific mutations arising spontaneously in stem cells (spermatogonia) lead to clonal expansion, resulting in elevated mutation levels in sperm over time. This process, termed selfish spermatogonial selection, explains the high spontaneous birth prevalence and strong paternal age-effect of disorders such as achondroplasia, Apert, Noonan and Costello syndromes, with direct experimental evidence currently available for specific positions of six genes (FGFR2, FGFR3, RET, PTPN11, HRAS and KRAS). We present a discovery screen to identify novel mutations and genes showing evidence of positive selection in the male germline, by performing massively parallel simplex PCR using RainDance technology to interrogate mutational hotspots in 67 genes (51.5 kb in total) in 276 biopsies of testes from 5 men (median age: 83 years). Following ultra-deep sequencing (~16,000x), development of a low-frequency variant prioritization strategy and targeted validation, we identified 61 distinct variants present at frequencies as low as 0.06%, including 54 variants not previously directly associated with selfish selection. The majority (80%) of variants identified have previously been implicated in developmental disorders and/or oncogenesis and include mutations in six newly associated genes (BRAF, CBL, MAP2K1, MAP2K2, RAF1 and SOS1), all of which encode components of RAS-MAPK pathway and activate signaling. Our findings extend the link between mutations dysregulating the RAS-MAPK pathway and selfish selection, and show that the ageing male germline is a repository for such deleterious mutations.

genetics↗

bioRxiv2018

Increased DNA methylation variability in rheumatoid arthritis discordant monozygotic twins

BackgroundRheumatoid arthritis is a common autoimmune disorder influenced by both genetic and environmental factors. Epigenome-wide association studies can identify environmentally mediated epigenetic changes such as altered DNA methylation, which may also be influenced by genetic factors. To investigate possible contributions of DNA methylation to the aetiology of rheumatoid arthritis with minimum confounding genetic heterogeneity, we investigated genome-wide DNA methylation in disease discordant monozygotic twin pairs.\n\nMethodsGenome-wide DNA methylation was assessed in 79 monozygotic twin pairs discordant for rheumatoid arthritis using the HumanMethylation450 BeadChip array (Illumina). Discordant twins were tested for both differential DNA methylation and methylation variability between RA and healthy twins. The methylation variability signature was then compared with methylation variants from studies of other autoimmune diseases and with an independent healthy population.\n\nResultsWe have identified a differentially variable DNA methylation signature, that suggests multiple stress response pathways may be involved in the aetiology of the disease. This methylation variability signature also highlighted potential epigenetic disruption of multiple RUNX3 transcription factor binding sites as being associated with disease development. Comparison with previously performed epigenome-wide association studies of rheumatoid arthritis and type 1 diabetes identified shared pathways for autoimmune disorders, suggesting that epigenetics plays a role in autoimmunity and offering the possibility of identifying new targets for intervention.\n\nConclusionsThrough genome-wide analysis of DNA methylation in disease discordant monozygotic twins, we have identified a differentially variable DNA methylation signature, in the absence of differential methylation in rheumatoid arthritis. This finding supports the importance of epigenetic variability as an emerging component in autoimmune disorders.

genomics↗

bioRxiv2017

Consequences Of Natural Perturbations In The Human Plasma Proteome

Proteins are the primary functional units of biology and the direct targets of most drugs, yet there is limited knowledge of the genetic factors determining inter-individual variation in protein levels. Here we reveal the genetic architecture of the human plasma proteome, testing 10.6 million DNA variants against levels of 2,994 proteins in 3,301 individuals. We identify 1,927 genetic associations with 1,478 proteins, a 4-fold increase on existing knowledge, including trans associations for 1,104 proteins. To understand consequences of perturbations in plasma protein levels, we introduce an approach that links naturally occurring genetic variation with biological, disease, and drug databases. We provide insights into pathogenesis by uncovering the molecular effects of disease-associated variants. We identify causal roles for protein biomarkers in disease through Mendelian randomization analysis. Our results reveal new drug targets, opportunities for matching existing drugs with new disease indications, and potential safety concerns for drugs under development.

genomics↗

bioRxiv2017

Causal Analyses, Statistical Efficiency And Phenotypic Precision Through Recall-By-Genotype Study Design

Genome-wide association studies have been useful in identifying common genetic variants related to a variety of complex traits and diseases; however, they are often limited in their ability to inform about underlying biology. Whilst bioinformatics analyses, studies of cells, animal models and applied genetic epidemiology have provided some understanding of genetic associations or causal pathways, there is a need for new genetic studies that elucidate causal relationships and mechanisms in a cost-effective, precise and statistically efficient fashion. We discuss the motivation for and the characteristics of the Recall-by-Genotype (RbG) study design, an approach that enables genotype-directed deep-phenotyping and improvement in drawing causal inferences. Specifically, we present RbG designs using single and multiple variants and discuss the inferential properties, analytical approaches and applications of both. We consider the efficiency of the RbG approach, the likely value of RbG studies for the causal investigation of disease aetiology and the practicalities of incorporating genotypic data into population studies in the context of the RbG study design. Finally, we provide a catalogue of the UK-based resources for such studies, an online tool to aid the design of new RbG studies and discuss future developments of this approach.

genetics↗

bioRxiv2016

Genome-wide Analysis of Differential Transcriptional and Epigenetic Variability Across Human Immune Cell Types

BackgroundA healthy immune system requires immune cells that adapt rapidly to environmental challenges. This phenotypic plasticity can be mediated by transcriptional and epigenetic variability.\n\nResultsWe applied a novel analytical approach to measure and compare transcriptional and epigenetic variability genome-wide across CD14+CD16- monocytes, CD66b+CD16+ neutrophils, and CD4+CD45RA+ naive T cells, from the same 125 healthy individuals. We discovered substantially increased variability in neutrophils compared to monocytes and T cells. In neutrophils, genes with hypervariable expression were found to be implicated in key immune pathways and to associate with cellular properties and environmental exposure. We also observed increased sex-specific gene expression differences in neutrophils. Neutrophil-specific DNA methylation hypervariable sites were enriched at dynamic chromatin regions and active enhancers.\n\nConclusionsOur data highlight the importance of transcriptional and epigenetic variability for the neutrophils key role as the first responders to inflammatory stimuli. We provide a resource to enable further functional studies into the plasticity of immune cells, which can be accessed from: http://blueprint-dev.bioinfo.cnio.es/WP10/hypervariability.

molecular biology↗