Mexico City Prospective Study: mapping genetic risk factors of major non-communicable diseases (MRC PHRU)
Genome-wide association studies (GWAS) have identified thousands of common and low frequency genetic variants associated with major non-communicable diseases (eg, cardiovascular disease and diabetes) as well as their major risk factors (eg, adiposity, blood pressure, blood lipids). However, the vast majority of these studies have been done in populations of European ancestry, which covers only a subset of human genetic diversity. Additional large studies of non-European populations are needed to fully assess the influence of genetics on disease.
The Mexico City Prospective Study (MCPS) is a blood-based prospective study of 150,000 adults who were recruited between 1998 and 2004 and have been followed for cause-specific mortality ever since. Questionnaire data and physical measurements were recorded at baseline, genome-wide genotyping and whole exome sequence data exists for all participants, and NMR metabolomics data (largely characterising blood lipid particles) exists in a large subset (currently 40,000, anticipated whole cohort by the time the project starts).
The specific DPhil project will be subject to further discussion and personal interest, but could include the following areas of work
- Conducting genome and exome-wide association studies of major non-communicable diseases (and/or their established major risk factors) after accounting for sources of genetic confounding within this population (i.e. genetic relatedness and admixture of distinct ancestral haplotypes);
- Assessing overlap of association results with known loci from other populations, and integrating results with regulatory features (e.g. molecular quantitative trait loci, chromatin states, etc.), pathway annotations or other external datasets to elucidate the functional basis for genetic risk factors;
- Evaluating shared aetiology of complex non-communicable diseases through genetic correlation analyses and phenome-wide association studies (PheWAS) that can identify genetic variants that exhibit pleiotropic effects on disease risk.
- Constructing population-specific polygenic risk scores (PRS) and assessing their utility in stratifying individuals by underlying genetic burden for disease and guiding prediction of disease outcomes.
RESEARCH EXPERIENCE, RESEARCH METHODS AND TRAINING
This project will involve detailed analysis and interpretation of existing MCPS data. The student will work within a multi-disciplinary team and will gain research experience in literature review, epidemiological and statistical methodology (including genetic epidemiology techniques), programming and data analysis. Regular research meetings and workshops will be held in which the candidate will be expected to attend and to present research findings.
FIELD WORK, SECONDMENTS, INDUSTRY PLACEMENTS AND TRAINING
The project will provide a range of training opportunities in statistical analysis and interpretation and statistical programming. By the end of the DPhil, it is expected that you will be competent to plan, undertake and interpret statistical analysis of large-scale epidemiological and genetic data, and to report your findings. The project will be based in the MRC Population Health Research Unit, Nuffield Department of Population Health, which has excellent facilities and a world-class community of statistical and clinical scientists.
Candidates should have a strong background in a mathematical or biomedical discipline and postgraduate training in epidemiology, statistics or public health. The project will involve large-scale data and statistical analyses. Candidates should therefore have an interest and aptitude in extending these skills as well as a strong interest in non-communicable disease epidemiology.