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Establishing causal relations for circulating factors to cardiometabolic and neurodegenerative diseases

Establishing causal relations for circulating factors to cardiometabolic and neurodegenerative diseases

Principal Investigator: Dr Tao Long
Approved Research ID: 57189
Approval date: March 9th 2020

Lay summary

Cardiometabolic and neurodegenerative diseases such as heart attack, diabetes, liver and kidney diseases, dementia including Alzheimer's continue to be the major devastating diseases in modern societies. Development of these diseases are complex, with important contributions from both genetic and environmental factors. Circulating factors in the blood, including small molecule metabolites, provide a snapshot into both genetic underpinnings and environmental exposures, and may serve as contributing factors that give rise to these diseases. Understanding how these diseases are influenced by circulating metabolites in blood will shed insight into the mechanisms of disease development and allow for discovery of novel therapeutics.

Previous studies in our laboratory using mass spectrometry based technologies have measured circulating metabolites in a few large human studies and identified blood metabolites that are associated with cardiometabolic and neurodegenerative disease phenotypes. Moreover, we have identified a number of common genetic variants that modulate levels of these key circulating metabolites. Here we propose to use genetic and disease outcome information from the UK Biobank participants to facilitate identification of key circulating metabolites that are causal to development of cardiometabolic and neurodegenerative diseases using Mendelian randomization methods.

We will further look for gene mutations that render extreme blood levels of these causal metabolites in some individuals that subsequently render higher risk of or protection from the diseases. These studies will identify blood metabolites causal to a multitude of cardiometabolic and neurodegenerative diseases. Furthermore, these studies will identify novel gene targets encompassing these diseases which could lead to the development of new therapeutics. Secondarily, our findings will revolutionize the means for early detection of impending disease development by screening for causal metabolites in the general population.