- Genetics and Genomics
- Cardiovascular Science
I work with clinical groups to design both family and population-based studies to investigate the genetic component of complex cardiovascular diseases
• essential hypertension - MRC BRIGHT project (and the Wellcome Trust Case Control Consortium - Nature 2007]
• familial coronary artery disease (CAD) - PROCARDIS [also see Hum Mol Genet 2007]
• pre-eclampsia - GOPEC [also see Am J Hum Genet 2005]
I participate in a Wellcome Trust funded genome-wide association (GWA) study to map susceptibility loci underlying ischemic cerebrovascular accidents (strokes) (project coordinator: Professor Hugh Markus at St. George's Medical School London)
I am a founder member of CHANGE, a study investigating the genetic basis of congenital heart disease and coordinated by collaborators at the Institute of Human Genetics in Newcastle. CHANGE is joining with other UK groups (including my departmental colleagues Shoumo Bhattachaya and Jamie Bentham) in plans for a GWA study of common variants associated with congenital heart disease.
Human quantitative genetic analysis
In the not so distant past, I enjoyed collaborating with Mark Lathrop, Director of the C.N.G. (Evry, France), Florent Soubrier (INSERM U525, Paris), the late Ryk Ward (formally head of the Dept. of Biological Anthropology in Oxford) and Roger Cox (MRC Harwell, UK) in a study of the quantitative genetics of the angiotensin-1 converting enzyme (ACE). This work was founded on the statistical analysis of haplotypes built from dozens of intragenic polymorphisms (predominantly single nucleotide polymorphisms or SNPs), and the measurement of effects on the quantitative ACE trait (activity) associated with particular haplotypes. We have been able to use information regarding ancestral recombination breakpoints to guide the model selection process, at least in European populations which have striking and interpretable patterns of linkage disequilibrium in this gene. Follow this link for a brief review of the ACE genetic mapping work and a summary of my thoughts on the nature of quantitative genetic variation.
One recurring theme of my research interests involves the ultimate resolution of genetic mapping of human QTL. This has focussed on the quantitative genetics of fetal hemoglobin, a further collaboration with Mark Lathrop and Swee-Lay Thein (KCL, London). Developing our high-resolution mapping strategy, we have saturated a QTL on chromosome 6q23 with informative markers, apply model selection procedures to identify a promising (multivariate) model and then confirmed that a haplotype model provides a satisfactory fit [Thein et al. PNAS 2007]. This allowed us to offer our "wet lab" experimental colleagues a shortlist of "hot SNPs" for functional evaluation - although this is not so simple where potentially transcriptionally active SNPs dominate the shortlist. We have also published results of a GWA study mapping novel F-cell QTL [Menzel et al. Nature Genetics 2007]
Other complex genetic diseases
I lead the statistical genetic analysis of the genome-wide gene-association study of asthma (child, adult and industrial asthma) and circulating IgE levels (a quantitative phenotype associated with asthma) through the GABRIEL project. Please see Moffatt et al. Nature 2007 for the results of a pioneering GWA study of childhood asthma. This EU FP6-sponsored research is supported by Ashish Kumar who provides informatics support to this project and by Sarah Keildson who holds a research studentship exploring statistcial genetic approaches to study gene-gene and gene-environmental interactions.
I have also participated in an EU consortium studying the genetic basis of clinical sequaelae of diabetes (EURAGEDIC) and a collaborative project funded by the UK MRC and National Kidney Research Fund (NKRF) to create a DNA bank to study genetic susceptibility to glomerulonephritis.
Strong genetic association between coronary artery disease (CAD) and SNPs on chromosome 9p in PROCARDIS (see Hum Mol Genet 2007 for details)