For a list of all publications, please see here.
Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus.
Stacey D*, Chen L*, Stanczyk PJ, Howson JMM, Mason AM, Burgess S, MacDonald S, Langdown J, […], Chilvers ER, Danesh J & Paul DS
Many individual genetic risk loci associate with multiple diseases; however, the molecular basis of these loci often remains unclear. We present an integrative approach to reveal the molecular mechanism underlying the PROCR locus, associated with lower coronary artery disease (CAD) risk but higher venous thromboembolism (VTE) risk. Using genetic analyses, we identified PROCR-p.Ser219Gly as the likely causal variant and protein C as a causal factor. Through human recall-by-genotype and in vitro experimentation, we showed that PROCR-219Gly leads to a perturbed protein C pathway with divergent downstream biological effects associated with the risk of CAD and VTE. The findings will inform therapeutic strategies targeting the protein C pathway.
Interleukin-6 receptor signalling and abdominal aortic aneurysm growth rates.
Paige E*, Clément M*, Lareyre F, Sweeting M, Raffort J, Grenier C, Finigan A, Harrison J, […], Freitag DF#, Paul DS# & Mallat Z#
The Asp358Ala variant in the interleukin-6 receptor (IL-6R) gene has been implicated in the development of abdominal aortic aneurysms (AAAs), but its effect on AAA growth over time is not known. In this study, 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. We found that 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, but there was no evidence of a reduction in AAA growth rate. 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. Our proof-of-principle data are compatible with the concept that IL-6 trans-signalling is relevant to AAA growth.
Genetic effects on promoter usage are highly context-specific and contribute to complex traits.
Alasoo K, Rodrigues J, Danesh J, Freitag DF, Paul DS# & Gaffney DJ#
Genetic variants that regulate RNA splicing and transcript usage have been implicated in both common and rare diseases. Although transcript usage quantitative trait loci have been mapped across multiple cell types and conditions, the molecular mechanisms through which these variants exert their effect have remained elusive. We performed a comprehensive analysis of RNA-sequencing data from human macrophages exposed to a range of inflammatory and metabolic stimuli, obtained from up to 84 individuals. We found 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 under-appreciated molecular mechanism mediating complex trait associations in a context-specific manner.
ProGeM: A framework for the prioritisation of candidate causal genes at molecular quantitative trait loci.
Stacey D, Fauman EB, Ziemek D, Sun BB, Harshfield EL, Wood AM, Butterworth AS, Suhre K & Paul DS
Quantitative trait locus (QTL) mapping of molecular phenotypes such as metabolites, lipids and proteins through genome-wide association studies (GWAS) represents a powerful means of highlighting molecular mechanisms relevant to human diseases. However, a major challenge of this approach is to identify the causal gene(s) at the observed QTLs. We present a novel analysis framework for the ‘Prioritisation of candidate causal Genes at Molecular QTLs’ (ProGeM), which incorporates biological domain-specific annotation data alongside genome annotation data from multiple repositories. We rigorously assessed the performance of ProGeM using a reference set of metabolite QTLs and provide a systematic benchmarking analysis of different functional annotation data sources.
Formalising recall by genotype as an efficient approach to detailed phenotyping and causal inference.
Corbin LJ, Tan VY, Hughes DA, Wade KH, Paul DS, Tansey KE, Butcher F, Dudbridge F, […], Danesh J, Franks PW & Timpson NJ
Detailed phenotyping is required to deepen our understanding of the biological mechanisms underlying genetic associations. In addition, the impact of potentially modifiable risk factors on disease requires analytical frameworks that allow causal inference. We discuss the characteristics of recall-by-genotype (RbG) as a study design aimed at addressing both these needs. We describe two broad scenarios for the application of RbG: studies using single variants and those using multiple variants. We consider the efficacy and practicality of the RbG approach, provide a catalogue of UK-based resources for such studies, and present an online RbG study planner.
Neutrophil-mediated IL-6 receptor trans-signaling and the risk of chronic obstructive pulmonary disease and asthma.
Farahi N*, Paige E*, Balla J, Prudence E, Ferreira RC, Southwood M, Appleby SL, Bakke P, […], Danesh J, Paul DS, Freitag DF# & Chilvers ER#
Interleukin-6 (IL-6), a pro-inflammatory cytokine, has been implicated in a range of complex chronic diseases. In this study, we investigated the role of the Asp358Ala functional variant, located in the interleukin-6 receptor (IL-6R) gene, in respiratory conditions such as chronic obstructive pulmonary disease (COPD) and asthma. We found that the Asp358Ala variant was associated with the risk of atopic asthma but not COPD. We showed that in carriers of the Asp358Ala minor allele shedding of soluble IL-6R from neutrophils and release of MCP-1 (a pro-inflammatory chemokine) in human pulmonary artery endothelial cells was increased. These findings suggest that neutrophils may be an important source of soluble IL-6R in the lungs and that the Asp358Ala variant may have pro-inflammatory effects.
Genome-wide analysis of differential transcriptional and epigenetic variability across human immune cell types.
Ecker E, Chen L, Pancaldi V, Bagger FO, Fernández JM, Carrillo de Santa Pau E, Juan D, Mann AL, […], Rico D#, Valencia A#, Beck S#, Soranzo N# & Paul DS#
A healthy immune system requires immune cells that adapt rapidly to environmental challenges. This phenotypic plasticity can be mediated by transcriptional and epigenetic variability. In the study, we applied a novel analytical approach to measure such variability genome-wide across three human immune cell types 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. Our data provide a resource to enable further functional studies into the plasticity of immune cells. Also, we recently published a review article on transcriptional and epigenetic variability.
Genetic drivers of epigenetic and transcriptional variation in human immune cells.
Chen L*, Ge B*, Casale FP*, Vasquez L*, Kwan T, Garrido-Martín D, Watt S, Yang Y, […], Paul DS, Stunnenberg HG, Stegle O, Downes K, Pastinen T# & Soranzo N#
Defining the multifaceted contribution of genetic and epigenetic factors to disease phenotypes is a major challenge in human genetics and medicine. In this study, we performed high-resolution genetic, epigenetic and transcriptomic profiling in three major human immune cell types from up to 197 individuals. We determined genetic effects on cell type-specific gene expression, splicing, DNA methylation and histone modifications through quantitative trait locus (QTL) mapping and allele-specific analyses. The data revealed specific, coordinated molecular events underpinning autoimmune disease risk.
Increased DNA methylation variability in type 1 diabetes across three immune effector cell types.
Paul DS*, Teschendorff AE*, Dang MA*, Lowe R*, Hawa MI, Ecker S, Beyan H, Cunningham S, […], Rakyan VK#, Beck S# & Leslie RD#
The incidence of type 1 diabetes is increasing, potentially implicating non-genetic factors such as epigenetic mechanisms in disease development. We conducted an epigenome-wide association study in 52 disease-discordant monozygotic twin pairs in three immune effector cell types. We found increased DNA methylation variability at genes associated with immune cell metabolism and the cell cycle. Our findings, based on 772 methylomes, implicate epigenetic changes that could contribute to disease pathogenesis in type 1 diabetes.
A donor-specific epigenetic classifier for acute graft-versus-host disease severity in hematopoietic stem cell transplantation.
Paul DS, Jones A, Sellar RS, Mayor NP, Feber A, Webster AP, Afonso N, Sergeant R, […], Rakyan VK#, Peggs KS# & Beck S#
Allogeneic haematopoietic stem cell transplantation (HSCT) is used to treat a variety of blood-related disorders. Acute graft-versus-host disease (aGVHD) is a prevalent immune-mediated complication following HSCT. Current diagnostic biomarkers that correlate with aGVHD severity, progression and therapy response in graft recipients are insufficient. In this study, we identified epigenetic marks in peripheral blood of healthy graft donors that correlate with aGVHD severity in sibling recipients before HSCT. Our findings suggest that epigenetic typing of HSCT donors in a clinical setting may be used to inform both donor selection and transplantation strategy.
Maps of open chromatin highlight cell type-restricted patterns of regulatory sequence variation at hematological trait loci.
Paul DS*, Albers CA*, Rendon A*, Voss K, Stephens J, HaemGen Consortium, van der Harst P, Chambers JC, Soranzo N, Ouwehand WH# & Deloukas P#
Nearly three-quarters of the genetic variants thus far identified to associate with red blood cell and platelet formation lie in non-protein-coding regions of the genome. In this study, we found that these variants are enriched in gene regulatory regions, marked by sites of open chromatin, specific to each different blood cell type. We focused on 13 genetic variants associated with platelet formation, finding that 10 of the variants acted by either creating or disrupting sites of protein binding. The findings from this study bring us one step closer to understanding the biology behind genetic variants linked to blood cell traits.
Seventy-five genetic loci influencing the human red blood cell.
van der Harst P*, Zhang W*, Mateo Leach I*, Rendon A*, Verweij N*, Sehmi J*, Paul DS*, Elling U*, […], Hicks AA#, Penninger JM#, Gieger C#, Kooner JS#, Ouwehand WH#, Soranzo N# & Chambers JC#
Anaemia is an important determinant of global ill health. To understand the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in over 135,000 individuals. We discovered 75 genetic regions associated with one or more red blood cell parameter. Using genome-wide maps of active DNA elements in red blood cells, we pinpointed 41 potential causal genetic variants. These findings provide new insights into molecular mechanisms and biological pathways controlling red blood cell formation and function.
A GWAS sequence variant for platelet volume marks an alternative DNM3 promoter in megakaryocytes near a MEIS1 binding site.
Nürnberg ST*, Rendon A*, Smethurst PA, Paul DS, Voss K, Thon JN, Lloyd-Jones H, Sambrook JG, […], Göttgens B, Soranzo N & Ouwehand WH
We describe the investigation of the molecular mechanism underlying the DNM3 gene region. This region harbours genetic variants that are associated with platelet volume. We found the gene regulatory protein MEIS1 to locate at an alternative transcription start site that is only used in platelet precursor cells. Further experimental analyses demonstrated the importance of DNM3 in platelet formation. The study provides an informative strategy of how to translate findings from genome-wide association studies into novel mechanistic insights.
Blood 120(24), 4859-4868 (2012)
Highlighted in Blood 120(24), 4666-4667 (2012)
Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome.
Albers CA*, Paul DS*, Schulze H*, Freson K, Stephens JC, Smethurst PA, Jolley JD, Cvejic A, […], Newbury-Ecob R#, Ouwehand WH# & Ghevaert C#
This study describes the discovery of a gene that causes thrombocytopenia with absent radii (TAR), a rare inherited blood and skeletal disorder. Genetic sequencing revealed that the syndrome occurs by a unique inherited mechanism, in which two gene regulatory variants lead to diminished RBM8A transcription. We found that low levels of Y14 (the protein encoded by RBM8A) affect platelet formation and cause TAR syndrome. The findings pave the way for prenatal diagnosis and genetic counselling in affected families.
Maps of open chromatin guide the functional follow-up of genome-wide association signals: application to hematological traits.
Paul DS, Nisbet JP, Yang TP, Meacham S, Rendon A, Hautaviita K, Tallila J, White J, […], Soranzo N, Ouwehand WH & Deloukas P
Turning genetic discoveries identified in genome-wide association studies into biological mechanisms is an important challenge in human genetics. We mapped sites of open chromatin, which mark active gene regulatory elements, in red blood and platelet precursor cells. Then, we screened these regions for genetic variants associated with red cell and platelet traits, and pinpointed several candidate functional variants. Using both cellular and mouse models, the study also describes the molecular mechanism at the PIK3CG gene region, implicated in the regulation of platelet volume and function.