Using genetic and phenotypic data to understand putative causal pathways leading to major human noncommunicable diseases.

Noncommunicable diseases account for more than 70% of the total human deaths worldwide. Cardiovascular diseases, cancers, chronic respiratory diseases, and diabetes are the four major types of noncommunicable diseases. Extrinsic exposures including but not limited to environmental, behavioral, occupational, lifestyle, metabolic factors have a major role in the development of most types of noncommunicable diseases. Over the past century, epidemiological studies have identified many risk factors for noncommunicable diseases. Yet several large randomized controlled trials designed to evaluate the efficacy of new therapies targeted at well-established risk factors for noncommunicable diseases have reported lower benefits than expected. Subsequent observational study of the same trial data has not clarified these unexpected findings. Thus, it is important and necessary to determine whether these well-established risk factors are causally associated with noncommunicable diseases before randomized controlled trials are conducted.
In this 36-month application, we aim to systematically investigate associations between extrinsic exposures and risk of major noncommunicable diseases and provide cumulative evidence for causal relationships. We will carry out a meta-analysis of prospective observational studies, a phenome-wide mendelian randomization analysis, and a meta-analysis of randomized clinical trials using data from UK Biobank, other public data sources, and published studies.
We will start analyses as soon as data becomes available and plan to finish this project and send manuscripts to co-authors for review within 18 months after we receive the data. We anticipate that this study will provide cumulative evidence for causal relationships between extrinsic exposures and risk of major noncommunicable diseases and help identify novel therapeutic targets for an improved prevention and treatment strategy for these complex diseases. Our study is consistent with the goal of UK Biobank that devotes to improving the prevention, diagnosis and treatment of a wide range of serious and life-threatening illnesses.