The goals of the Atherogenomics Laboratory are to develop a comprehensive and integrated understanding of the genetic and molecular etiology of complex phenotypes, with a focus on coronary artery disease (CAD) and obesity. This entails simultaneous application of a number of methodologies, including rigorous clinical and metabolic phenotyping, genetics, tissue-specific gene expression, integrative genomics, and functional assays.
Genetic Origins of Coronary Heart Disease
Coronary artery disease (CAD), the leading cause of death in the western world, is a heritable condition not fully explained by known risk factors. We first identified a common allele on chromosome 9p21 robustly associated with CAD (Science 2007). In subsequent studies in collaboration with other groups, over 45 common genetic variants that cumulatively increase CAD risk have been identified. We now have comprehensive phenotypic and genetic data on over 10,000 individuals with or without premature CAD. We continue to mine these data using bioinformatic approaches and laboratory based studies to obtain a better understanding of the biological basis of this important disease.
Genetics of Human Obesity
In collaboration with Dr. Robert Dent, of the Weight Management Clinic at The Ottawa Hospital, we have recruited a population of over 3,000 severely obese individuals and 1,000 age and gender matched ultra-lean subjects. We have identified several novel rare variants contributing to an obesity phenotype. More recently, using DNA microarrays followed by 1000 Genomes imputation, we have obtained data on more than 20 thousand common genetic variants. This project involves a close collaboration with Drs. Mary-Ellen Harper (PhD), at the University of Ottawa, and Katey Rayner (PhD) to unravel the complex genetic, genomic and metabolic basis of obesity and its response to intervention.
Metabolic and Anatomical Phenotyping
Precise and accurate phenotyping is key to deciphering the relationship of genetic variants to complex disease. For CAD studies, we collaborate closely with Drs. Marino Labinaz (MD) and Derek So (MD) , in the cardiac catheterization laboratory and with Dr. Benjamin Chow (MD) in the CT angiography lab. For studies related to obesity, we work closely with Dr. Robert Dent in the Weight Management Clinic at the Ottawa Hospital.
Techniques include genome wide assocation studies using the Affymetrix 6.0 array, carried out in the John & Jennifer Ruddy Cardiovascular Genetics Laboratory in collaboration with Dr. Alex Stewart (PhD) and in the GeneChip facility in the Atherogenomics Laboratory. SNP genoptyping is performed using a range of techniques including high throughput TaqMan assays using Roche LightCycler technology and resequencing approaches. Regions of high potential functionality that are likely to encompass disease-causative variants can now be subjected to deep sequencing using the Roche GX FLX 454 sequencer.
One of the challenges of genetic epidemiology is to identify causative genetic variants that contribute significantly to disease etiology. We use a range of bioinformatics approaches, including eQTL information and public databases, generated by the ENCODE and Roadmap Epigenomics projects to identify functional regulatory elements to be followed up with more specific methodologies, including chromatin immunoprecipitation sequencing and DNase I hypersensitive site sequencing. Thus, we can determine whether a risk locus is likely to harbor functional cis-acting regulatory modules whose activity is altered by a particular risk variant prior to standard molecular biology approaches in the laboratory. Other bioinformatic approaches include pathway and topological analyses of GWAS data.
Molecular and Cellular Analyses
Bioinformatically predicted function of DNA regions are then validated at the cellular and biochemical level using a range of conventional approaches from promoter and enhancer assays to CHiP and Chirp and functional studies in cell types relevant to atherosclerosis, including human aortic endothelial cells and human aortic smooth muscle cells. Current studies are focused on the COL4A1/COL4A2, SMAD3, ZC3HC1 and TRIB1 loci for CAD.
See Research Gate profile.
- Shungin D et al (including McPherson R as one of 280 authors). New genetic loci link adipose and insulin biology to body fat distribution. Nature. 2015 Feb 12;518(7538):187-96
- Do R et al (including McPherson R as one of 93 authors). Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature. 2015 Feb 5;518(7537):102-6.
- Myocardial Infarction Genetics Consortium Investigators (including McPherson R as one of 93 authors). Inactivating mutations in NPC1L1 and protection from coronary heart disease. N Engl J Med. 2014 Nov 27;371(22):2072-82.
- Cole CB, Nikpay M, Lau P, Stewart AF, Davies RW, Wells GA, Dent R, McPherson R. Adiposity significantly modifies genetic risk for dyslipidemia. J Lipid Res. 2014; Sep 15.
- Davies RW, Lau P, Naing T, Nikpay M, Doelle H, Harper ME, Dent R, McPherson R. A 680 kb duplication at the FTO locus in a kindred with obesity and a distinct body fat distribution. Eur J Human Genet 2013;21:1417-22.
- Davies RW, Wells GA, Stewart AFR, Erdmann J, Shah SH, Ferguson JF, Hall AS, Anand SS, Burnett MS, Epstein SE, Dandona S, Chen L, Nahrstaedt J, Loley C, König IR, Kraus WE, Granger CB, Engert JC, Hengstenberg C, Wichmann HE, Schreiber S, Tang WHW, Ellis SG, Rader DJ, Hazen SL, Reilly MP, Samani NJ, Schunkert H, Roberts R, McPherson R. A genome wide association study for coronary artery disease identifies a novel susceptibility locus in the major histocompatibility complex. Circulation – Cardiovascular Genetics 2012;5:217-225
- Schunkert H, König IR, Kathiresan S, Reilly MP, Assimes TL, …. Thorsteinsdottir U, O'Donnell CJ, McPherson R, Erdmann J; the CARDIoGRAM Consortium, Samani NJ. (RM: a senior author). Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nature Genetics 2011; 43:333-338.
- Ghosh S, Dent R, Harper ME, Gorman S, Stuart J, McPherson R. Blood gene expression reveals pathway differences between diet-sensitive and resistant subjects prior to caloric restriction. Obesity 2011;19:457-63
- Jarinova O, Stewart AFR, Roberts R, Wells GA, Lau P, Naing T, Buerki C, McLean BW, Cook RC, Parker JS, McPherson R. Functional analysis of the chromosome 9p21.3 coronary artery disease risk locus. Arterioscler Thrombos Vasc Biol 2009;29:1671-1677.
- McPherson R, Pertsemlidis A, Kavaslar N, Stewart A, Roberts R, Cox DR, Hinds D, Pennacchio LA, Tybjaerg-Hansen A, Folsom AR, Boerwinkle E, Hobbs HH, Cohen JC. A common allele on chromosome 9 associated with coronary heart disease. Science 2007;316:1488-1491.
Current Team Members
Sebastien Soubeyrand, PhD: Senior Research Associate & Laboratory Manager
Paulina Lau, MSc: Senior technician
Amy Martinuk, MSc: Technician
Heather Doelle, BSc, MLT: Genetics recruiter
Adam Turner, BSc: Graduate student
Tara Linseman, BSc: Graduate Student