Exploring cardiovascular genetics in mid versus later life to improve understanding of biological mechanisms and clinical risk prediction. Biomedical Science, Funded PhD Ref: 5350

Project Description

Cardiovascular disease (CVD) in the UK increases in prevalence from 5% in middle age to over 20% in people aged 75+. Age affects many clinical features as well as the impact of these risk factors on CVD and resulting outcomes. Patient management is also complicated by increasing multimorbidity and polypharmacy as people age. When searching for genetic determinants of CVD risk, previous genome-wide association studies (GWAS) predominantly focus on mid-life participants and simply adjust for age. However, it is known that risk varies with age, and subsets of individuals with higher genetic susceptibility have substantially greater disease risk.

The primary research aim is to determine mechanisms influencing CVDs and risk factors that vary by age, for example in different age strata (i.e., mid vs. later life). This information will inform progress towards more person-centred approaches for risk assessment and disease management (a life course genetics approach), and to identify new targets for intervention.

As the PhD researcher on this project, you will develop advanced skills and understanding in genetic epidemiology: combining data science with Big Data on linked genetics and electronic medical records from hundreds of thousands of individuals. This inter-disciplinary PhD will contribute to the University of Exeter research programmes on human genetics, cardiovascular and cardiometabolic disease, ageing, multimorbidity, and pharmacogenetics. Your supervisory team at the University of Exeter includes experts in human genetics, cardiovascular diseases, statistical analysis, and data science.

Data: This research will primarily use data from two large human cohorts: 1) UK Biobank, a cohort of 500,000 individuals with genetics and electronic medical records: the number aged 75+ in the follow-up is increasing, providing novel opportunities for this research. The team has access to the data, extensive experience and preparatory phenotyping already undertaken, and ethical approval is in place; 2) Our Future Health has recruited 1 million participants, with 5 million planned by 2026, and include genetic and medical records linkage. Further replication in the ethnically-diverse All of US cohort will be sought.

Objectives:

1. Clarify shared and distinct mechanisms of specific cardiovascular diseases and relevant risk factors in different age groups. For example, genetic analysis (GWAS) of risk factor interactions with age, or cerebrovascular disease in <65-year-olds vs >75-year-olds. Analysis will also include genetic correlations between risk factors measured at different ages, and identification of the distinct and shared causal variants (colocalisation). PhD chapters would focus on disease domains, such as coronary heart disease, cerebrovascular disease, and vascular dementia.

2. Investigate polygenic scores for risk factors measured in different age strata with respect to prediction of individual outcomes, moving towards a personalised approach. (For this we will use GWAS in a training set, and a separate testing set for the polygenic score prediction testing).

3. Utilise the whole genome sequencing data to determine the pathogenic effect of rare variants in candidate genes on early/late cardiovascular disease diagnosis, such as the LDLR gene implicated in familial hypercholesterolemia, or NOTCH3 implicated in CADASIL. We hypothesise that the penetrance of known and novel variants will vary by age strata, impacting age of onset.

We anticipate the findings to inform future research into a more personalised approach to cardiovascular risk and disease management in later life.

As part of your training, you will be expected to present your work at national and international conferences and publish in topic-relevant peer reviewed journals. Our audience will be primarily researchers and clinicians, but we will also disseminate our findings to patients and the public (with support from our PPI group). In addition, you will participate in research meetings focused on cardiovascular disease, genetics, and ageing, giving you the opportunity to learn from experts in the field and build lasting relationships with your peers.

The studentship will be awarded on the basis of merit. Students who pay international tuition fees are eligible to apply, but should note that the award will only provide payment for part of the international tuition fee (~£24k) and no stipend.

International applicants need to be aware that they will have to cover the cost of their student visa, healthcare surcharge and other costs of moving to the UK to do a PhD.

The conditions for eligibility of home fees status are complex and you will need to seek advice if you have moved to or from the UK (or Republic of Ireland) within the past 3 years or have applied for settled status under the EU Settlement Scheme.