Mendelian randomization: the contribution of genetic epidemiology to elucidating environmentally modifiable causes of disease

Author(s):  
George Davey Smith ◽  
Shah Ebrahim
2017 ◽  
Author(s):  
Lavinia Paternoster ◽  
Kate Tilling ◽  
George Davey Smith

The past decade has been proclaimed as a hugely successful era of gene discovery through the high yields of many genome-wide association studies (GWAS). However, much of the perceived benefit of such discoveries lies in the promise that the identification of genes that influence disease would directly translate into the identification of potential therapeutic targets (1-4), but this has yet to be realised at a level reflecting expectation. One reason for this, we suggest, is that GWAS to date have generally not focused on phenotypes that directly relate to the progression of disease, and thus speak to disease treatment.


2015 ◽  
Vol 79 (3-4) ◽  
pp. 194-204 ◽  
Author(s):  
Andreas Ziegler ◽  
Henry Mwambi ◽  
Inke R. König

2019 ◽  
Vol 65 (3) ◽  
pp. 427-436 ◽  
Author(s):  
Pedrum Mohammadi-Shemirani ◽  
Jennifer Sjaarda ◽  
Hertzel C Gerstein ◽  
Darin J Treleaven ◽  
Michael Walsh ◽  
...  

Abstract BACKGROUND Identifying markers of chronic kidney disease (CKD) that occur early in the disease process and are specific to loss of kidney function rather than other underlying causes of disease may allow earlier, more accurate identification of patients who will develop CKD. We therefore sought to identify diagnostic blood markers of early CKD that are caused by loss of kidney function by using an innovative “reverse Mendelian randomization” (MR) approach. METHODS We applied this technique to genetic and biomarker data from 4147 participants in the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial, all with known type 2 diabetes, impaired fasting glucose, or impaired glucose tolerance. Two-sample MR was conducted using variants associated with creatinine-based eGFR (eGFRcrea) from the CKDGen Consortium (n = 133814) to estimate the effect of genetically decreased eGFRcrea on 238 serum biomarkers. RESULTS With reverse MR, trefoil factor 3 (TFF3) was identified as a protein that is increased owing to decreased eGFRcrea (β = 1.86 SD per SD decrease eGFRcrea; 95% CI, 0.95–2.76; P = 8.0 × 10−5). Reverse MR findings were consistent with epidemiological associations for incident CKD in ORIGIN (OR = 1.28 per SD increase in TFF3; 95% CI, 1.18–1.38; P = 4.58 × 10−10). Addition of TFF3 significantly improved discrimination for incident CKD relative to eGFRcrea alone (net reclassification improvement = 0.211; P = 9.56 × 10−12) and in models including additional risk factors. CONCLUSIONS Our results suggest TFF3 is a valuable diagnostic marker for early CKD in dysglycemic populations and acts as a proof of concept for the application of this novel MR technique to identify diagnostic biomarkers for other chronic diseases. ClinicalTrials.gov Identifier NCT00069784


2021 ◽  
Vol 50 (Supplement_1) ◽  
Author(s):  
Miriam Mosing ◽  
Bronwyn Brew ◽  
Alison Gibberd ◽  
Malin Ericsson ◽  
Kelli Lehto ◽  
...  

Abstract Focus and outcomes for participants Long periods between exposures and outcomes pose a number of challenges for life course epidemiological research, including unmeasured confounding factors (e.g.; familial factors) and mediation by other covariates, which make it difficult to unequivocally establish associations let alone causality. In this symposium we will present a number of different studies based on big data utilizing a variety of methods to overcome some of the issues encountered in research across long time frames or generations. Our focus will be on the different methods, the solutions they provide as well as their limitations. The methods presented were applied in the context of life course epidemiology and include: mediation analyses; genetic epidemiology; well-established and novel family designs including twins, siblings and cousins, and a method comparable to Mendelian randomization - ICE FALCON (Inference on Causation from Examination of Familial Confounding) which is part of a more general approach called ICE CRiSTAL (Inference on Causation from Examining Changes in Regression coefficients in STatistical AnaLsyes). The intended outcomes for the audience are to increase awareness of the challenges imposed by the data frequently used in this field of research and present possible solutions to (at least partly) address those. It is our intention to generate discussion and encourage other researchers to share their experiences and solutions to increase knowledge collectively. Rationale for the symposium, including for its inclusion in the Congress The main theme of the conference is ‘Methodological Innovations in Epidemiology’. Our symposium includes six different methods to strengthen causal inferences in epidemiology. While some of the presented methods are well established in classic epidemiology research (i.e. mediation analyses), others are more commonly found in different disciplines such as the expanding genetic epidemiology field (e.g. alternative twin designs and measured genetic risk approaches). In addition, we are presenting a new method for making inference about causation developed by Prof. John Hopper and Dr Shuai Li and co-workers called ICE FALCON, which applies to twin and family data and is part of a more general approach called ICE CRiSTAL. These methods use observational data to infer or rebut causality between measured variables, similar to Mendelian randomization (without relying on genetic information or strong assumptions). All the work presented is either nearing publication or has been published in the last two years and each presenter is intimately involved with the analysis and methods they will be presenting. Beyond a range of methods and study designs we have also a diversity of researchers and research questions in our symposium by including: researchers at different stages in their career and from around the world (ranging from early Postdoctoral Fellows over Senior Research Fellows/Assistant professors to Professors); a variety of research questions and diseases; and a range of population context including Indigenous Australians, babies, children, and adults, in order to appeal to a wider audience. Presentation program 6 talks of 8 minutes each with 2 minutes for questions followed by a general discussion facilitated by the chair. Names of presenters Dr Miriam A Mosing1,2


2003 ◽  
Vol 358 (1438) ◽  
pp. 1701-1708 ◽  
Author(s):  
Newton E. Morton

Genetic epidemiology developed in the middle of the last century, focused on inherited causes of disease but with methods and results applicable to other traits and even forensics. Early success with linkage led to the localization of genes contributing to disease, and ultimately to the Human Genome Project. The discovery of millions of DNA markers has encouraged more efficient positional cloning by linkage disequilibrium (LD), using LD maps and haplotypes in ways that are rapidly evolving. This has led to large international programmes, some promising and others alarming, with laws about DNA patenting and ethical guidelines for responsible research still struggling to be born.


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