Project ID CM-HD2023_45

ThemeCM-HD

Co Supervisor 1A Department of Twin Research and Genetic Epidemiology, School of Life Course and Population ScienceWebsite

Co Supervisor 1B Department of Twin Research and Genetic Epidemiology, School of Life Course and Population ScienceWebsite

Multi-omics to understand the genetic and molecular mechanisms of Type 2 Diabetes subtypes

Type 2 Diabetes (T2D) and obesity-related traits are global epidemics. In the UK alone, ~4 million people are living with diabetes and 10% of the NHS budget is spent on diabetes. A limitation to early detection and treatment of T2D is its diverse clinical presentation and response to medication. Improved methods for stratification of patients would have a large clinical impact. Genome wide association studies (GWAS) have identified genetic variants associated with T2D, and there is much excitement in using Polygenetic Risk Scores (PRS) to predict risk of disease from genetic data. Clinical subtypes of T2D have been linked to different genetic variants, suggesting the molecular drivers of disease may differ across genetic subtypes.

This project will leverage large biobanks, electronic health records and ‘omic profiling to 1) identify the molecular signature of T2D genetic subtypes and 2) determine if PRS predictive ability is increased by combining genetic and ‘omic data to predict disease.

Objectives:
1. Define Type 2 Diabetes clinical subtype Polygenic Risk Scores in TwinsUK and other datasets with available ‘omic data (transcriptomics from adipose, skin, gut and blood, plus epigenetics, proteomics, metabolomics, and microbiome) to identify ‘omic signatures associated with genetic risk of different Type 2 Diabetes subtypes.
2. Evaluate subtype specific ‘omic signatures for disease mechanisms and links to therapeutic targets
3. Construct combined PRS and ‘omics risk score (including baseline and trajectories over time) to test for improved ability to predict future development or disease progression of T2D.

One representative publication from each co-supervisor:

• Adipose- and maternal- specific regulatory variants at KLF14 influence type 2 diabetes risk in women via a female-specific effect on adipocyte size and body composition. Nature Genetics 2018 Apr;50(4):572-580. doi: 10.1038/s41588-018-0088-x.

• Adipose methylome integrative-omic analyses reveal genetic and dietary metabolic health drivers and insulin resistance classifiers. Genome Medicine 2022, in press.