Omics regulation of blood pressure variability and its causal role for vascular disease

Additional Supervisor: Prof Yudi Pawitan (Karolinska Institute)

Background

Variability of blood pressure (BP) appears to be associated with various cardiovascular and cerebrovascular conditions. Such variability is not limited to the difference between systolic BP (SBP) and diastolic BP (DBP), i.e. pulse pressure, but also the individual variability of SBP and DBP.

In the last 5 years, a number of lines of evidence have shown that genetic variants can contribute to the variability or uniformity of complex traits, not only to the magnitude or measure of the trait (e.g. Shen et al. 2012; Yang et al. 2012). Statistically speaking, these variants show genetic variance heterogeneity effects on the complex traits. Such loci have been termed "vQTL" (Rönnegård & Valdar 2010), and can be identified via genome-wide association studies (GWAS). They remain, however, very understudied.

The variability of a phenotype was often studies as variance heterogeneity between different genotypes. With multiple measurements of the same individual, e.g. data collected in the UK Biobank, we can also assess variability of BP within individuals. Although the number of repeated measurements is not big, the great sample size still provides substantial statistical power.

We are leading a UK Biobank project (No. 14302) to study phenotypic variability of various obesity-related phenotypic outcomes, where the large sample size provides us great power to identify novel vQTL. This provides us the unique opportunity to investigate the genetic basis of the variability of individual SBP and DBP. Furthermore, we can finally use the vQTL as instruments in Mendelian Randomisation and other designs to infer the causality between variability of BP on cardiovascular and cerebrovascular disease or related phenotypes.

Through a close Edinburgh-Stockholm collaboration, we are now able to not only link GWAS discoveries to human plasma proteins, but also map the proteomic profile of BP QTL and vQTL onto single extracellular vesicles (EVs). Integrative omics can be subsequently performed to predict EV markers that may help future diagnosis/prognosis of vascular disease (analog to single-cell analysis for complex traits, e.g. Lake et al. 2018).

Aims

The aim of this project is to apply novel genome-wide association tests for phenotypic variability to identify genomic loci that regulate the variability of BP. A powerful worldwide meta-analysis can also be performed in collaboration with our consortium partners. The identified vQTL for BP will be subsequently analysed to assess causal effects of the variability of BP on vascular disease and related phenotypes. Via our Edinburgh-Stockholm collaboration, we will also design single-EV proteomics panel to predict potential human plasma EV markers for vascular disease. We aim to assist diagnosis/prognosis of cardiovascular and cerebrovascular disease based on BP variability measurement and omics markers.

Training Outcomes

Upon completion of this project, the PhD candidate is expected to achieve the following items:

- High-quality publications in international peer-reviewed journals;
- Broad and deep knowledge of medical (gen)omics;
- A depth of experience in statistical computation including widely used genomic and statistical software packages and languages such as R and Python.
- Ability to develop new analysis pipelines for medical genetic and omic analysis;
- Ability to process big data for diverse interdisciplinary scientific projects.

This MRC programme is joint between the Universities of Edinburgh and Glasgow. You will be registered at the host institution of the primary supervisor detailed in your project selection.

All applications should be made via the University of Edinburgh, irrespective of project location:

http://www.ed.ac.uk/studying/postgraduate/degrees/index.php?r=site/view&id=919

Please note, you must apply to one of the projects and you are encouraged to contact the primary supervisor prior to making your application. Additional information on the application process if available from the link above.

For more information about Precision Medicine visit:

http://www.ed.ac.uk/usher/precision-medicine