PhD: (Epi)genetic informed gene prioritisation for small vessel disease

Reading Time: 4 minutes

Print This Post

03/12/2025

no comments

PhD
London SW7 2AZ
Posted 2 days ago

Website Imperial College London

Closing date: 9th January

@imperialcollegeldn.bsky.social

PhD studentship at Imperial College London with Alexi Nott on vascular and immune contributors to dementia through multiomic study of small vessel disease.

An opportunity has arisen for a 4-year PhD studentship within the Department of Brain Sciences at Imperial College London, funded by the Alzheimer’s Society VIDA DTC. VIDA (Vascular and Immune contributors to DementiA) is a multi-institutional partnership between Alzheimer’s Society and four world-leading research sites: the University of Manchester, University of Edinburgh, Imperial, and City St George’s University of London. With projects focussing on the importance of vascular and immune mechanisms in dementia, VIDA PhD students will become the next generation of much-needed dementia researchers, contributing to breakthroughs in dementia diagnosis and treatment.

VIDA students will embark upon a 4-year fully-funded PhD project at one of the four institutions above, with access to the state-of-the-art research facilities and interdisciplinary training available at all sites. Students at each site will come together as a cohort at several points during the programme, including annual conferences and residential workshop retreats, which will link in with other Alzheimer’s Society Doctoral Training Centres across the UK. Students will also participate in engagement schemes with the Alzheimer’s Society and beyond, sharing the impact of their research in the community. The programme also benefits from built-in opportunities for placements with leading industrial partners, and bespoke training plans including schemes to develop teaching, mentoring, and grant writing skills.

Project Description:

Cerebral small vessel disease (SVD) is a major cause of stroke and vascular dementia, and a key contributor to Alzheimer’s disease (AD). It affects the brain’s smallest blood vessels, arterioles, capillaries, and venules, leading to pathologies such as cerebral amyloid angiopathy (CAA) and arteriolosclerosis. Clinically, SVD is characterised by white matter hyperintensities (WMHs), lacunes, microbleeds, and enlarged perivascular spaces. Early vascular dysfunction, including impaired cerebral blood flow and increased blood–brain barrier (BBB) permeability, is strongly linked to dementia onset and progression. While circulating biomarkers (e.g. VEGF, ICAM1, PDGFB, EDN1) correlate with imaging features of SVD, no single, robust blood biomarker currently exists.

Genome-wide association studies (GWAS) show that both SVD and AD are highly heritable, sharing several genetic loci such as APOE. Most disease-associated variants are noncoding and likely influence gene regulation. Epigenomic analyses have shown that AD heritability is enriched in microglia and myeloid cells, whereas SVD heritability localises to endothelial, mural, and astrocytic cells, which are key components of the neurovascular unit. Moreover, recent multitrait analyses have revealed shared loci between AD and cardiovascular disease, including PLEC and C1Q, implicating overlapping vascular and immune pathways. However, large-scale studies defining gene regulatory mechanisms in SVD and underlying common genetic mechanisms with cardiovascular traits and other dementias remain unexplored.

We hypothesise that integrative multiomic analyses of SVD blood samples will uncover novel molecular mechanisms, biomarkers, and therapeutic targets. Objective 1 will identify gene regulatory mechanisms that are dysregulation in SVD. DNA methylation and RNA-seq will be generated from 147 longitudinally phenotyped SVD blood samples (Mild Stoke Study 2 [MSS2] cohort), with matched genotype, proteomic, and neuroimaging data. Analyses will identify DNA methylation and gene expression changes associated with SVD subtypes, dementia progression, and polygenic risk, including cross-comparison with age-, sex-, and cardiovascular risk-matched controls from the AIRWAVES cohort. Objective 2 will prioritise genetic determinants of SVD. Multitrait analysis with cardiovascular traits, together with quantitative trait locus and Mendelian randomisation analyses will link causal variants to altered gene regulation. Cross-integration with histone modification (CUT&Tag) and single-cell multiomic data alongside plasma proteomics will refine biomarker and drug target prioritisation.

This project will deliver the first integrative map of gene regulatory mechanisms in SVD, linking human genetics to molecular function. These findings will accelerate biomarker discovery and enable genetically validated therapeutic strategies for SVD and vascular dementias.

Application process:

Applicants must hold (or obtain by October 2026) a first or upper-second-class honours degree or equivalent in a neuroscience, computational neuroscience or cardiovascular science or related discipline. A Master’s degree in a related research is highly desirable but not essential. Applicants must also meet Imperial College’s English language requirements – further details can be found at https://www.imperial.ac.uk/study/pg/apply/requirements/english/. All Imperial College London PhD entry requirements must be met.

Applicants should submit their CV and a cover letter, including full contact details of two referees, to Dr Alexi Nott, a.nott@imperial.ac.uk . Once shortlisted, the applicant will undergo an interview by the VIDA management board. The successful applicant will subsequently need to formally apply online (Link). We regret that due to the large volume of applications received, we are only able to notify those shortlisted for interview.