Mendelian randomization to hypothesis-free causal inference

Lead Research Organisation: University of Bristol

Abstract

Obtaining reliable evidence on causes of disease and influences on disease progression is problematic, since many other factors than the ones under study may influence the outcomes. Using genetic variants that mimic potentially modifiable factors that may cause disease or influence its course has become a widely-used approach to improving such understanding. Known as “Mendelian randomization” the methodology is still under development. This programme of work will contribute to strengthening the reliability of the approach, and, in particular, investigate the application to identifying treatments for existing disease.

Technical Summary

Background: The MRC Integrative Epidemiology Unit (MRC-IEU) has pioneered the Mendelian randomization (MR) approach, which is now showing exponential growth in terms of breadth of application and number of publications. This has been fuelled by the coalescence of four trends (1) the rapid increase in the number of identified genetic variants related to exposures of interest to clinical investigators; (2) the maturation of UK Biobank and other large-scale population studies with accessible data, including from genome wide association study (GWAS) analysis; (3) the expansion in available data from GWAS consortia; and (4) the popularization of 2-sample MR analyses (2SMR), which allow causal estimates to be made from summary level data. We have developed a range of new methods that allow stronger inference to be drawn from MR studies and released a platform (MR-Base) for high-throughput 2SMR analysis. Both have been rapidly taken up by the scientific community. Our aims will considerably expand the range of questions that MR can address, include:
Aim 1: To increase the clinical utility of MR by conducting studies of disease progression, which will provide MR evidence that speaks directly to disease treatment
Aim 2: To develop approaches that subject the MR assumptions to further scrutiny through negative controls and the assessment of pleiotropy, together with developing structural equation modelling as a flexible strategy for analysis of MR studies
Aim 3: To conduct MR studies in family based data, which provides additional robustness checks, and allows estimation of maternal and paternal influences on offspring outcomes
Methods: The three aims will be advanced in parallel, within a programme that will utilise simulation, substantive analysis, replication and triangulation of evidence.
Translation will be facilitated by the new NIHR Bristol Biomedical Research Centre (Davey Smith Scientific Director) and through expanding our collaborations with industry.

Publications

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Kemp JP (2019) A Metabolic Screen in Adolescents Reveals an Association Between Circulating Citrate and Cortical Bone Mineral Density. in Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

 
Description Response to consultation on 'Adding Folic Acid to Flour' by UK Government
Geographic Reach National 
Policy Influence Type Participation in a national consultation
 
Description (BIOMAP) - Biomarkers in Atopic Dermatitis and Psoriasis
Amount € 20,884,846 (EUR)
Funding ID 821511 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 04/2019 
End 03/2024
 
Description Characterising the relationship between NAFLD and T2D using genetic insights.
Amount kr 4,000,000 (DKK)
Funding ID NNF180C0031650 
Organisation Novo Nordisk 
Sector Private
Country Denmark
Start 06/2018 
End 05/2022
 
Description Confidence in Global Mental Health
Amount £173,000 (GBP)
Funding ID MR/R019622/1 
Organisation University of Bristol 
Sector Academic/University
Country United Kingdom
Start 03/2018 
End 04/2019
 
Description Identifying maternal and fetal genetic determinants of infant birthweight and their relationship to offspring cardiometabolic risk
Amount $3,679,200 (USD)
Funding ID APP1157714 
Organisation National Health and Medical Research Council 
Sector Public
Country Australia
Start 01/2019 
End 12/2021
 
Description Investigating the differential geographical, sociodemographic and genetic predictors of mental illness and wellbeing using longitudinal survey data
Amount £99,888 (GBP)
Funding ID ES/T009101/1 
Organisation Economic and Social Research Council 
Sector Public
Country United Kingdom
Start 01/2020 
End 12/2020
 
Description Is there a causal link between primary open angle glaucoma and dementia?
Amount £14,852 (GBP)
Funding ID SGA18_011 
Organisation Fight for Sight 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2019 
End 01/2020
 
Description MICA: NURTuRE - changing the landscape of renal medicine to foster a unified approach to stratified medicine
Amount £2,561,603 (GBP)
Funding ID MR/R013942/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 07/2018 
End 07/2022
 
Description Metabolomically healthy obesity" in the age of high-throughput metabolomics: Studying personalized medicine in 30,000 individuals.
Amount 2,026,128 kr (SEK)
Organisation Danish Council for Independent Research 
Sector Public
Country Denmark
Start 08/2019 
End 07/2022
 
Description The causal map of the human phenome.
Amount £809,240 (GBP)
Funding ID 208806 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2018 
End 03/2023
 
Description The role of bone and joint size and shape in explaining common musculoskeletal diseases.
Amount £1,565,599 (GBP)
Funding ID 209233 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2018 
End 08/2023
 
Description Use of Mendelian randomisation to examine the role of abnormal hip shape in the development of hip osteoarthritis
Amount £243,926 (GBP)
Funding ID MR/S021280/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 09/2019 
End 08/2022
 
Description Blog - Does Schizophrenia Influence Cannabis Use? How to report the influence of disease liability on outcomes in Mendelian Randomization studies. - G Davey Smith 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Does Schizophrenia Influence Cannabis Use? How to report the influence of disease liability on outcomes in Mendelian Randomization studies. January 2019.
https://targ.blogs.bristol.ac.uk/2019/01/07/does-schizophrenia-influence-cannabis-use-how-to-report-the-influence-of-disease-liability-on-outcomes-in-mendelian-randomization-studies/
Year(s) Of Engagement Activity 2018
 
Description Bristol Festival of Economics: Genoeconomics 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact We hosted a panel discussion on genoeconomics as part of the Bristol Festival of Ideas. This even was well attended by a range of participants and had Neil Davies, George Davey Smith and Fleur Meddens on the panel. We discussed the implications of recent discoveries in genetic epidemiology for economics and social science more generally.
Year(s) Of Engagement Activity 2019
URL https://www.ideasfestival.co.uk/events/genoeconomics/
 
Description Even low alcohol consumption is bad news for strokes 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact News artical in the following publications Guardian, CNN, BBC, Medical News Today, USA Today, Daily Mail, Telegraph, Scotsman, Sun, Star, Web MD, Daily Sabah, Irish Independent, USA Today etc
Year(s) Of Engagement Activity 2019
URL https://www.theguardian.com/society/2019/apr/04/even-low-booze-consumption-is-bad-news-for-strokes-s...
 
Description FUTURES event with stands from UoB STEM researchers, including IEU toolkits (Question generator, Sample sizer, Wheel of Fortune, Chromosome) and ALSPAC activities. Part of European Researchers' Night organised by central PE team. 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact FUTURES event with stands from UoB STEM researchers, including IEU toolkits (Question generator, Sample sizer, Wheel of Fortune, Chromosome) and ALSPAC activities. Part of European Researchers' Night organised by central PE team.
Year(s) Of Engagement Activity 2019
URL http://www.bristol.ac.uk/integrative-epidemiology/news/2019/futures-2019.html
 
Description Introductory Mendelian Randomization Workshop. Public Health Grand Rounds. UCLA Fielding School of Public Health, Los Angeles. 31st May 2019. 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Mendelian randomization (MR) utilizes the particular properties of germline genetic variation to strengthen causal inference with respect to modifiable influences on health, disease and social outcomes. This session will present the assumptions required for MR and the ever-expanding range of sensitivity analyses and falsification strategies that are available. Hypothesis-free causal search strategies based on MR will be briefly touched upon, as will the application of MR to molecular and tissue-specific phenotypes.
Year(s) Of Engagement Activity 2019
URL https://ph.ucla.edu/events/dept-epidemiology-introductory-mendelian-randomization-workshop
 
Description Launch of new blog on causality in population health 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact IEUREKA! is for blog posts on causality in population health from the MRC Integrative Epidemiology Unit. It provides IEU researchers with a platform to synthesis research findings into short articles and discussion pieces and to express their views on current public interest topics. We aim to reach the wider public.
Year(s) Of Engagement Activity 2019
URL https://ieureka.blogs.bristol.ac.uk/
 
Description Mendelian Randomization Workshop. University Medical Centre, Groningen. 14th October 2019. 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact This workshop will cover issues relevant to applied causal inference in epidemiology, building on practical examples across diverse fields. The value of formal approaches to quantitative causal inference will be explored in the context of such practical examples. The use of falsification methods (including negative control exposures & outcomes and cross-context comparisons) and the harnessing of external perturbations (including formal instrumental variables analyses) will be discussed. A triangulation approach based on a pre-specified set of methods - each which may be biased, but with biases anticipated to be near-orthogonal - will be advanced. The notion that causal inference will always be a joint qualitative and quantitative activity, and that quantification of causal estimates should go as far as is useful, but no further, will be defended. The focus will be mainly on non-genetic approaches to causal inference, as a second workshop will cover Mendelian randomization in detail.
Year(s) Of Engagement Activity 2019
URL https://www.rug.nl/aletta/calendar/workshop-george-davey-smith---triangulation-of-evidence-and-causa...
 
Description Methods for strengthening causal interference in examining mediation between socioeconomic position and health outcomes. Do we need a better data base for research on social inequality in health, education, welfare and democratic participation? 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Professor George Davey Smith attending this presentation in Norway on 'Methods for strengthening causal interference in examining mediation between socioeconomic position and health outcomes. Do we need a better data base for research on social inequality in health, education, welfare and democratic participation? This raised the profile of his research at University of Bristol.
Year(s) Of Engagement Activity 2018
URL https://videoportal.rcn.no/#/videos/b65c1186-c423-40ec-9c93-f2d5e5f6f473
 
Description News articles about research: Higher education reduces the risk of heart attack 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact News coverage in the following newspaper; Daily Mail (UK), Daily Telegraph, Classic 105, Siasat Daily, Asian News International, Devdiscourse, New Kerala, Web India 123, Ani News, Business Standard India, New Delhi News, World News Update, Pulse Today, MSN Philippines
Year(s) Of Engagement Activity 2019
URL https://www.dailymail.co.uk/health/article-7058455/The-longer-spend-education-likely-overweight-unhe...
 
Description Part of MRC Festival of Medical Research - talks from researchers about their work, followed by conversations 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Other audiences
Results and Impact Talks from researchers about their work, followed by conversations at the Friendly Club, Westbury on Trym
Year(s) Of Engagement Activity 2019
 
Description Part of MRC Festival of Medical Research - very short talks from researchers about their work, followed by carousel of 4 toolkit activities 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Very short talks from researchers about their work, followed by carousel of 4 toolkit activities at the Nova Primary School, Avonmouth
Year(s) Of Engagement Activity 2019
 
Description Part of MRC Festival of Medical Research - very short talks from researchers about their work, followed by carousel of 4 toolkit activities 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Policymakers/politicians
Results and Impact Very short talks from researchers about their work, followed by carousel of 4 toolkit activities at St Pius RC Primary School, Withywood
Year(s) Of Engagement Activity 2019
 
Description Pint of Science in Bristol 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Industry/Business
Results and Impact Talk in local pub in Bristol on Nature versus Nutrition
Year(s) Of Engagement Activity 2019
URL https://pintofscience.co.uk/city/bristol
 
Description Presentation at Academy of Medical Sciences Mentoring Scheme - G Davey Smith 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact Professor George Davey Smith gave a presentation at Early Career Team Scientist. Succeeding in Team Science: Collaboration, recognition and leadership in London in May 2018. This talk raised the profile of Professor Davey Smith and his research.
Year(s) Of Engagement Activity 2018
 
Description Presentation at American Society of Human Genetics - G Davey Smith 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Professor George Davey Smith was invited to present at the American Society of Human Genetics. San Diego, California. Talk entitled "Mendelian randomization and disease progression: Challenges and opportunities". October 2018.

This talk raised the profile of Professor Davey Smith and his research.
Year(s) Of Engagement Activity 2018
 
Description Presentation at Montreal Neurological Institute and Hospital - G Davey Smith 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Professor George Davey Smith was invited to present at the Montreal Neurological Institute and Hospital, McGill University. The Genome Centre. Montreal on "Mendelian Randomization: some unresolved issues". 7th September 2018.

This talk raised the profile of Professor Davey Smith and his research.
Year(s) Of Engagement Activity 2018
 
Description Presentation at Norwegian Epidemiology Association's conference - G Davey Smith 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Professor George Davey Smith was invited to present at the Norwegian Epidemiology Association's conference. Trondheim. 15th November 2018. Title "Mendelian Randomization and the potential of genetics to inform causality"

This talk raised the profile of Professor Davey Smith and his research.
Year(s) Of Engagement Activity 2018
 
Description Presentation at Open Targets Integration Meeting - G Davey Smith 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Professor George Davey Smith was invited to be present at the Open Targets Integration Meeting. Hinxton on "Mendelian randomization: an update". June 2018.

This talk raised the profile of Professor Davey Smith and his research.
Year(s) Of Engagement Activity 2018
 
Description Presentation at Opening Symposium Centre for Fertility and Health - G Davey Smith 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Professor George Davey Smith was invited to give a talk on "Can genetics contribute to the study of fertility and health? Opening Symposium Centre for Fertility and Health. Oslo. May 2018.

This talk raised the profile of Professor Davey Smith and his research.
Year(s) Of Engagement Activity 2018
 
Description Presentation at Statens Institute for Folkesundhed. Copenhagen - G Davey Smith 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Professor George Davey Smith was invited to give a presentation on "Triangulation of evidence: strengthening causal inference in observational epidemiology" at the Statens Institute for Folkesundhed. April 2018

This talk raised the profile of Professor Davey Smith and his research.
Year(s) Of Engagement Activity 2018
 
Description Presentation at University of California - G Davey Smith 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Professor George Davey Smith was invited to present at the University of California, USA. Title of talk "Using genetics to understand modifiable behavioural, social and physiological causes of disease". October 2018. This talk raised the profile of Professor Davey Smith and his research.

This talk raised the profile of Professor Davey Smith and his research.
Year(s) Of Engagement Activity 2018
 
Description Presentation at the Bristol Poverty Institute. Fifth Peter Townsend Memorial Conference - G Davey Smith 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Professor George Davey Smith was invited to present at the Bristol Poverty Institute, Fifth Peter Townsend Memorial Conference. University of Bristol. November 2018. Title "Causal Analysis of Social Inequalities in Health".

This talk raised the profile of Professor Davey Smith and his research.
Year(s) Of Engagement Activity 2018
 
Description Presentation at the Common Disease Meeting - G Davey Smith 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Professor George Davey Smith was invited to give a presentation at the Common Disease Meeting. Oxford, UK. Title "G=E, GrE and GxE: opportunities for epidemiology".

This talk raised the profile of Professor Davey Smith and his research.
Year(s) Of Engagement Activity 2018
 
Description Presentation at the Norwegian Institute of Public Health - G Davey Smith 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Professor George Davey Smith was invited to give a presentation titled "What Epidemiologists and Demographers can learn from each other: An Epidemiologist's Perspective" at The Norwegian Institute of Public Health. Oslo. May 2018.

This talk raised the profile of Professor Davey Smith and his research.
Year(s) Of Engagement Activity 2018
 
Description Presentation at the University of Bristol - G Davey Smith 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Professor George Davey Smith was invited to present at the SRSM2018 Pre-conference workshop: Causal Inference for Research Synthesis. University of Bristol, Bristol. July 2018.

This talk raised the profile of Professor Davey Smith and his research.
Year(s) Of Engagement Activity 2018
 
Description Presented Precision Medicine Webinar - G Davey Smith 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Asked to present "What is Mendelian Randomization and How Can it be Used as a Tool for Medicine and Public Health? Opportunities and Challenges". For the Precision Medicine Webinar. 27th November 2018.
Year(s) Of Engagement Activity 2018
URL https://www.youtube.com/watch?v=pc3uQz06gO8&feature=youtu.be&app=desktop
 
Description Stand in Einstein's Garden including 15 giant stuffed chromosomes to decorate and IEU toolkits (Question generator, Sample sizer, Wheel of Fortune, Mystery Box, Confounders) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Stand in Einstein's Garden including 15 giant stuffed chromosomes to decorate and IEU toolkits (Question generator, Sample sizer, Wheel of Fortune, Mystery Box, Confounders)
Year(s) Of Engagement Activity 2019
URL http://www.bristol.ac.uk/integrative-epidemiology/news/2019/green-man-2019.html
 
Description Triangulation of evidence and causal inference in epidemiology workshop. University Medical Centre, Groningen. 16th October 2019. 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Triangulation of evidence and causal inference in epidemiology workshop. University Medical Centre, Groningen. 16th October 2019.
Year(s) Of Engagement Activity 2019