Watkins group

Research Overview

Molecular genetics: Our studies focus on the molecular basis of monogenic cardiomyopathies to provide insight into disease processes in heart muscle. Most disease-genes for hypertrophic cardiomyopathy (HCM) encode contractile proteins, but an important new finding was our demonstration of the first non-sarcomeric disease-gene for HCM: the y-2 subunit of the AMP-activated protein kinase (AMPK). Studies in inherited dilated cardiomyopathy (DCM) have also lead to the identification of sarcomeric mutations, but also have identified abnormalities in calcium-handling proteins.

Functional analysis: Biochemical, biophysical, and gene-targeting analysis of mutant contractile proteins have lead us to propose that there is no unifying defect in contractility underlying HCM. Instead, we have postulated that HCM is a disease of energetic compromise (because the various mutations increase the energy cost of force production). This hypothesis has been supported by clinical MR spectroscopy measurements in patients and has implications, which we are now exploring, for treatment and for common forms of cardiac hypertrophy and failure.

Translational research: The disease-gene identification programme in our research lab has now been translated into the first NHS molecular diagnostic service for inherited "sudden cardiac death syndromes".

Coronary artery disease: The PROCARDIS Study consortium has, over the last seven years, assembled the largest collection worldwide of families with early myocardiac infarction. This five-centre, four-country, consortium (with pharmaceutical and biotechnology partners) is coordinated by Professor Watkins with John Peden, Fiona Green and Martin Farrall. A substantial genome-wide linkage screen has been completed and linkage loci are being evaluated and a high-density genome-wide SNP analysis is near completion. A unique aspect for the collection is a very large trio family-based population for TDT analysis (1200 trio families) which is unrivalled in this late onset disorder. The major investment over recent years should yield exciting opportunities for genetic and functional analysis over the next five years.

Recent Publications

Peden, J.F., Hopewell, J.C., Saleheen, D. & other authors 2011. 'A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease'. (2011) Nat Genet. Mar 6. [Epub ahead of print] View on Pubmed
Clarke, R., Peden, J. F., Hopewell, J. C. & other authors 2009. 'Genetic variants associated with Lp(a) lipoprotein level and coronary disease', N Engl J Med 361, 2518-2528. View on Pubmed
Carballo S, Robinson P, Otway R, Fatkin D, Jongbloed JD, de Jonge N, Blair E, van Tintelen JP, Redwood C, Watkins H. 2009, 'Identification and Functional Characterization of Cardiac Troponin I As a Novel Disease Gene in Autosomal Dominant Dilated Cardiomyopathy', Circ Res. vol 105, no 4, pp 375-82. View on Pubmed
Marston S, Copeland O, Jacques A, Livesey K, Tsang V, McKenna WJ, Jalilzadeh S, Carballo S, Redwood C, Watkins H. 2009, 'Evidence From Human Myectomy Samples That MYBPC3 Mutations Cause Hypertrophic Cardiomyopathy Through Haploinsufficiency' Circ Res. vol 105, no 3, pp 219-22. View on Pubmed
Elliott P, Chambers JC, Zhang W, Clarke R, Hopewell JC, Peden JF, Erdmann J, Braund P, Engert JC, Bennett D, Coin L, Ashby D, Tzoulaki I, Brown IJ, Mt-Isa S, McCarthy MI, Peltonen L, Freimer NB, Farrall M, Ruokonen A, Hamsten A, Lim N, Froguel P, Waterworth DM, Vollenweider P, Waeber G, Jarvelin MR, Mooser V, Scott J, Hall AS, Schunkert H, Anand SS, Collins R, Samani NJ, Watkins H, Kooner JS. 2009, 'Genetic Loci associated with C-reactive protein levels and risk of coronary heart disease.' JAMA. vol 302, no 1, pp 37-48. View on Pubmed
Newton-Cheh C, Johnson T, Gateva V, Tobin MD, Bochud M, Coin L, Najjar SS, Zhao JH, Heath SC, Eyheramendy S, Papadakis K, Voight BF, Scott LJ, Zhang F, Farrall M, Tanaka T, Wallace C, Chambers JC, Khaw KT, Nilsson P, van der Harst P, Polidoro S, Grobbee DE, Onland-Moret NC, Bots ML, Wain LV, Elliott KS, Teumer A, Luan J, Lucas G, Kuusisto J, Burton PR, Hadley D, McArdle WL; Wellcome Trust Case Control Consortium, Brown M, Dominiczak A, Newhouse SJ, Samani NJ, Webster J, Zeggini E, Beckmann JS, Bergmann S, Lim N, Song K, Vollenweider P, Waeber G, Waterworth DM, Yuan X, Groop L, Orho-Melander M, Allione A, Di Gregorio A, Guarrera S, Panico S, Ricceri F, Romanazzi V, Sacerdote C, Vineis P, Barroso I, Sandhu MS, Luben RN, Crawford GJ, Jousilahti P, Perola M, Boehnke M, Bonnycastle LL, Collins FS, Jackson AU, Mohlke KL, Stringham HM, Valle TT, Willer CJ, Bergman RN, Morken MA, Döring A, Gieger C, Illig T, Meitinger T, Org E, Pfeufer A, Wichmann HE, Kathiresan S, Marrugat J, O'Donnell CJ, Schwartz SM, Siscovick DS, Subirana I, Freimer NB, Hartikainen AL, McCarthy MI, O'Reilly PF, Peltonen L, Pouta A, de Jong PE, Snieder H, van Gilst WH, Clarke R, Goel A, Hamsten A, Peden JF, Seedorf U, Syvänen AC, Tognoni G, Lakatta EG, Sanna S, Scheet P, Schlessinger D, Scuteri A, Dörr M, Ernst F, Felix SB, Homuth G, Lorbeer R, Reffelmann T, Rettig R, Völker U, Galan P, Gut IG, Hercberg S, Lathrop GM, Zelenika D, Deloukas P, Soranzo N, Williams FM, Zhai G, Salomaa V, Laakso M, Elosua R, Forouhi NG, Völzke H, Uiterwaal CS, van der Schouw YT, Numans ME, Matullo G, Navis G, Berglund G, Bingham SA, Kooner JS, Connell JM, Bandinelli S, Ferrucci L, Watkins H, Spector TD, Tuomilehto J, Altshuler D, Strachan DP, Laan M, Meneton P, Wareham NJ, Uda M, Jarvelin MR, Mooser V, Melander O, Loos RJ, Elliott P, Abecasis GR, Caulfield M, Munroe PB. 2009, 'Genome-wide association study identifies eight loci associated with blood pressure.' Nat Genet. 2009 May 10. [Epub ahead of print] View on Pubmed

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Research Areas

Cardiovascular Disease

Genomics

Statistical Genetics

Keywords

Molecular Genetics, Molecular Biology, Heart Muscle Disease, Complex Cardiovascular Phenotypes, Coronary Artery Disease

Funding

British Heart Foundation

The Wellcome Trust

EC Framework 6