To see a list of all publications, please click here.
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. However, identifying specific transcriptional effects of these variants remains challenging, partly because reference transcriptomes are incomplete and contain many truncated transcripts that lack annotated 3′ or 5′ ends. We developed a novel analytical approach to overcome these limitations by stratifying transcript annotations into three separate components: promoters, internal exons and 3′ ends. We apply our method to genomic and transcriptomic data from human macrophages exposed to a range of inflammatory stimuli and a metabolic stimulus, obtained from up to 84 individuals. We found that over half of the quantitative trait loci (QTLs) colocalising with complex traits were identified only at the transcript level with no detectable effect on total gene expression. We highlight how different RNA-sequencing quantification approaches capture distinct aspects of transcription and that characterizing the full spectrum of transcriptional consequences of genetic variation requires a combination of analytical strategies.
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 provided a systematic benchmarking analysis of different functional annotation data sources.
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 soluable IL-6R in the lungs and 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, see our review 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 the 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 prior to 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 a main determinant of global ill health. To understand elucidate 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 a number of 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.