Heritability and family-based GWAS analyses to discover novel lipidomic biomarkers of cardiovascular disease

There is a need to identify more discriminatory biomarkers to guide and personalise therapy for cardiovascular disease. Of particular interest are biomarkers with a strong genetic influence (ie exhibiting high heritability), as they may identify novel causal pathways for intervention through “Mendelian randomisation”. Although many novel species are now measurable using omics technologies, in general their heritability is unknown, as family-based studies have not been performed.

Hypothesis: Analysis of lipidomic profiles in intensively phenotyped nuclear families with GWAS data available will identify particularly heritable lipidomic biomarkers, discover causative genetic variation, and prioritise the development of specific phenotypic assays for use in largescale epidemiological studies.

Objectives: Measure lipidomic profiles in plasma samples from nuclear families collected in an ongoing family-based study of the genetics of cardiovascular risk factors with 20 year follow-up. Determine the heritability of these species and identify particularly heritable novel biomarkers. Carry out GWAS analysis in families to discover novel associations. Determine the association between heritable biomarkers and cardiovascular risk in the cohort.

Methods: The family cohort (250 families, 1400 individuals) was established in 1993-1996, and has undergone detailed phenotyping both at baseline and at two subsequent recalls (2000 and 2006). Plasma has been stored from baseline and each recall at -80C. Phenotyping includes 24 hour blood pressure, measurements of carotid atheroma, echocardiography and cardiac magnetic resonance scanning. The cohort is flagged for mortality. GWAS data has been generated using the Illumina 660W-Quad chip. The cohort has demonstrated adequate power to detect genetic influences on moderately heritable phenotypes at GWAS significance (eg plasma lipids, angiotensin-converting enzyme levels, urate). Profiling of the plasma lipidome (e.g. phospholipids, sphingolipids, eicosanoids, endocannabinoids) will be undertaken using mass spectrometry-based lipidomics assays developed by our group. We will then use standard statistical genetics approaches to determine heritability and carry out GWAS analyses of the most heritable lipidomic species. Strong candidate genes in associated regions will be sequenced for rare large-effect variants. Specific assays for species of interest will be developed.

Potential Outcomes/Impacts: Identification of genetic variation influencing the most heritable subset of lipidomic biomarkers. Downstream, Mendelian randomisation studies to confirm that these cause cardiovascular disease, in the UK Biobank or other suitable cohorts. Thereby, the identification of novel therapeutic targets.

The project offers excellent opportunity for cross-cutting skills to be developed. The successful candidate's first laboratory experience will be to carry out the lipidomic measurements, which will expose him/her to state-of-the-art technologies in the Nicolaou lab. He/she will then develop analysis skills both with regard to the phenotypic data (Nicolaou) and contribute to the GWAS analysis (Keavney). They will then return to the genetics laboratory (Keavney) to conduct sequencing studies for rare variation in GWAS identified regions. The project offers a comprehensive training in the study of genotype-phenotype relationships in complex diseases.

This 4-year full-time studentship forms one of our PhD opportunities within the MRC Doctoral Training Partnership (MRC DTP) scheme. Funding provides full support for tuition fees, annual tax-free stipend at Research Council UK rates (currently £13, 863) and conference/travel allowance. The project is due to commence October 2015 and is open to UK/EU nationals only due to the nature of the funding.

Applicants should hold (or expect to obtain) a minimum upper-second honours degree (or equivalent) in biochemistry, genetics, pharmacology, pharmaceutical chemistry or related medical/health science. A Masters qualification in a similar area would be an advantage.

Please direct applications in the following format to Professor Bernard Keavney ([Email Address Removed]):

• Academic CV
• Official academic transcripts
• Contact details for two suitable referees
• A personal statement (750 words maximum) outlining your suitability for the study, what you hope to achieve from the PhD and your research experience to date.

Any enquiries relating to the project and/or suitability should be directed to Professor Keavney. Applications are invited up to and including 26 November 2014.

Further details on the MRC DTP scheme, shortlisting/interview process and additional PhD project opportunities can be found on our website: www.mhs.manchester.ac.uk/mrcdtp

http://www.cardiovascular.manchester.ac.uk/staff/bernardkeavney

www.mhs.manchester.ac.uk/mrcdtp
http://www.mhs.manchester.ac.uk/postgraduate/mhs-graduate-school/