We have been using genome-wide association and sequencing approaches to identify genes with a role in obesity, type 2 diabetes and related quantitative traits, as well as rare extreme forms of these diseases. More recently, we have also focused on expanding these studies to populations of non European ancestry, exploring the rarer allele spectrum, as well as initiating studies of host genetics of infection. To further the knowledge from a statistical association to a biologically relevant finding it is imperative to determine the functional implications of those variants in terms of protein structure, activity and action in vivo. To functionally evaluate those genes with genetic and statistical associations with disease will be the next great challenge in complex disease. We have established collaborations with other Sanger Institute researchers, and have the ability to study novel genes implicated in disease in model organisms such as mouse (Sanger Institute Mouse genetics programme). The ultimate aim will be to elucidate how those variants are acting at the cellular and organismal level to increase individual predisposition to disease.
1) Genome-wide Association Studies
We work with many other groups across the world in large consortia, such as MAGIC (Meta-Analyses of Glucose and Insulin-related traits Consortium) and GIANT (Genetic Investigation of ANthropometric Traits), that aim to increase statistical power by performing meta-analyses of GWAS data across many different studies. Within these efforts we are involved in large-scale trans-ethnic meta-analyses for de novo discovery and fine-mapping, including analyses of rarer alleles both through arrays targeting exome, as well as incorporating imputation from large reference panels (1000genomes, UK10K and HRC).
We are members of the UK Biobank CardioMetabolic Consortium (UKBCMC), where we will be using genome-wide genotype and biomarker data on the ~500K UK Biobank individuals to investigate cardiometabolic traits and diseases and are co-leading the HbA1c effort.
Our new effort in studies of host genetics in infection include a genome-wide association study of scarring trachoma in Gambians (collaboration with Dr David Mabey, Professor Robin Bailey and Professor Dominic Kwiatkowski at WTSI) to identify human polymorphisms that predispose to scarring and potentially identify molecules and mechanisms that play an important role in either protection or pathogenesis of this disease.
In collaboration with Professor IS Farooqi at the University of Cambridge Metabolic Research Laboratories, we are also genotyping 1,600 individuals with persistent thinness from the STudy Into Lean and Thin Subjects (STILTS). These participants have body mass index <18 kg/m2 in the absence of any medical problems or eating disorders. They are being genotyped on a high-density array with increased coverage of exonic regions, enabling us to search for both common & rare variants that confer resistance to obesity in an obesogenic society.
Furthermore, in collaboration with the genetic epidemiology group of Manj Sandhu, and the viral genomics group of Paul Kellam, we are working on a large population cohort from rural Uganda and conducting GWAS aimed at identification of novel loci for mutliple cardiometabolic and infectious traits (including KSHV, EBV), and fine-mapping of known loci, associated with disease related quantitative traits.
In parallel, we are also developing methods for the overlap analysis of two (or more) traits with the aim of identifying variants that are associated with both traits, and applying these to empirical data.
2) Next Generation Sequencing
In collaboration with Professor Stephen O'Rahilly, Dr David Savage, Dr Rob Semple and Professor Sadaf Farooqi we have conducted many candidate gene sequencing projects in patients with severe insulin resistance and severe childhood onset obesity, which have led to the discovery of causal mutations underlying the phenotype in affected individuals. These approaches have been superseded by whole-exome sequencing approaches, including within the UK10K project, using next generation sequencing techniques, for a number of patients with syndromes of insulin resistance and severe childhood onset obesity. This will allow us to conduct unbiased approaches to identify novel rare variants (mutations) that may underlie or contribute to these extreme forms of disease.
3) Model Organisms
In addition to the phenotyping of knockout lines generated as part of the Sanger Zebrafish Mutation Project and Mouse Genetics Project, we are also using CRISPR-Cas9 technology in both mouse and zebrafish to investigate the function of novel genes implicated in disease. As well as more classical knockout generation, this system allows us to model specific mutations identified in patients with metabolic disease, to investigate their role in protein function and disease progression.
See full list of publications in this link: