Principal Investigator: Miss Louise Millard
Department: School of Social and Community Medicine
Institution: University of BristolTags: 16729, BMI, causality, Mendelian randomization, MR-pheWAS
1a: We aim to test a novel method for identifying potentially causal associations, which we call the Mendelian randomisation phenome-wide association study (MR-pheWAS) approach. We aim to identify potentially causal effects of BMI, as an exemplar.
We have tested the MR-pheWAS approach using the Avon Longitudinal Study of Parents and Children (ALSPAC) dataset (with ~8K participants). Repeating this with Biobank will greatly improve statistical power, and means we investigate causal effects in adulthood.
Research question: What novel, potentially causal effects of BMI can the MR-pheWAS approach identify?
Health conditions: Body mass index, and several other traits.
1b: BMI is associated with a wide range of diseases. This project aims to improve understanding of the complex effects of BMI, by testing for the causal effects of BMI on a wide range of outcomes. Results from this project will prioritize a subset of hypotheses for replication and further investigation.
Identifying potentially causal effects of BMI is important in order to inform policy makers on appropriate interventions. Interventions targeted at BMI are likely to impact a wide range of traits and diseases. This is becoming increasingly important as the UK is now experiencing increasing levels of obesity.
1c: We will use data of all participants from Biobank that have measurements for BMI and a set of genetic loci that have previously been found to be associated with BMI.
We will test the causal effect of BMI on a wide range of outcomes. We will do this using a natural experiment (instrumental variable) constructed from the genome (a Mendelian randomization approach), to identify outcomes that may be affected by BMI.
We use a hypothesis-free approach and so will test a large arbitrarily selected set of outcomes, rather than selecting particular outcomes.
1d: All participants with a value for BMI (var=21001) and BMI associated genetic loci.
- Approved 03/08/2016:
|We would like to run MR-pheWAS analyses for the following traits (with field IDs):
• Blood pressure
• Female Puberty
• Male Puberty
• Type 2 Diabetes
• Genetic variants / phenotypes for which we would like to run the MR-pheWAS first stage only, that is the direct tests of genetic score on the set of outcomes, such that an actual variable for the phenotype is not needed –
o AHRR methylation
• Blood measures – when the data becomes available
- Approved 05/08/2016:
|We would like to run MR-pheWAS analyses for the following traits:
• Prostate cancer
- Approved 13/10/2016:
|We would like to run our pheWAS analysis with a set of additional genetic variants, provided in the attached file. We have evidence to suggest that these variants may have a regulatory impact on the S1PR1 gene, which we hypothesise to have a functional role on the aetiology of cardiovascular health. In the absence of any genetic associations with relevant traits thus far, we would like to undertake a pheWAS to potentially formulate new hypotheses and develop our understanding of S1PR1.|
- Approved 15/12/2016:
|We would like to submit an amendment, in order to investigate the usefulness of a new method for instrumental variable estimation based on a penalization-likelihood approach that was recently proposed by Kang et al (2016), on real Mendelian randomization studies. We will, as an exemplar, re-examine the causal relationship between BMI (exposure) and blood pressure (outcome) using the Kang (2016) method, as the positive causal relationship between these two variables is well-established.
The hope is that the new robust method will still reaffirm this causal relationship, but now with robustness guarantees in case some of the genetic instruments are invalid. In addition, the new method can detect which instruments are invalid, which could be informative for future research using BMI variants in Mendelian randomization. Hence, this work will feed into our MR-pheWAS analyses by informing the choice of instrumental variable method to use, and also informing which genetic variants are invalid instruments and we may wish to remove from our analyses.
The outcome is blood pressure (systolic or diastolic), the exposure is BMI, the instruments are genetic variants of BMI, and confounding variables are sex and age (with a quadratic term).
- Approved 10/05/2017:
|We would like to perform a MR-pheWAS of Alzheimer disease, using a genetic risk score.|
Lead Collaborator: Professor Guido Imbens
Graduate School of Business
655 Knight Way
Stanford CA 94305-5015
United States of America
Last updated May 12, 2017