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      Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians

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      Author(s): 1 , 2 , 1 , 3 , 4 , 5 ,   1 , 2 , 6 ,
      Publication date (Electronic):
      Journal: The BMJ
      Publisher: BMJ Publishing Group Ltd.

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          Abstract

          Mendelian randomisation uses genetic variation as a natural experiment to investigate the causal relations between potentially modifiable risk factors and health outcomes in observational data. As with all epidemiological approaches, findings from Mendelian randomisation studies depend on specific assumptions. We provide explanations of the information typically reported in Mendelian randomisation studies that can be used to assess the plausibility of these assumptions and guidance on how to interpret findings from Mendelian randomisation studies in the context of other sources of evidence

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          'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease?

          George Davey Smith, Shah Ebrahim (2003)
          Associations between modifiable exposures and disease seen in observational epidemiology are sometimes confounded and thus misleading, despite our best efforts to improve the design and analysis of studies. Mendelian randomization-the random assortment of genes from parents to offspring that occurs during gamete formation and conception-provides one method for assessing the causal nature of some environmental exposures. The association between a disease and a polymorphism that mimics the biological link between a proposed exposure and disease is not generally susceptible to the reverse causation or confounding that may distort interpretations of conventional observational studies. Several examples where the phenotypic effects of polymorphisms are well documented provide encouraging evidence of the explanatory power of Mendelian randomization and are described. The limitations of the approach include confounding by polymorphisms in linkage disequilibrium with the polymorphism under study, that polymorphisms may have several phenotypic effects associated with disease, the lack of suitable polymorphisms for studying modifiable exposures of interest, and canalization-the buffering of the effects of genetic variation during development. Nevertheless, Mendelian randomization provides new opportunities to test causality and demonstrates how investment in the human genome project may contribute to understanding and preventing the adverse effects on human health of modifiable exposures.
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            An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans

            Robert Scott, Laura J. Scott, Reedik Mägi … (2017)
            To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 × 10−8), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action–associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.
            Article 0 comments Cited 329 times – based on 0 reviews     Review now
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              Exome-wide association study of plasma lipids in >300,000 individuals

              Dajiang J Liu, Gina M. Peloso, Haojie Yu … (2017)
              We screened DNA sequence variants on an exome-focused genotyping array in >300,000 participants with replication in >280,000 participants and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice revealed lipid changes consistent with the human data. We utilized mapped variants to address four clinically relevant questions and found the following: (1) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease; (2) outside of the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (3) only some mechanisms of lowering LDL-C seemed to increase risk for type 2 diabetes; and (4) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (e.g., TM6SF2, PNPLA3) tracked with higher liver fat, higher risk for type 2 diabetes, and lower risk for coronary artery disease whereas TG-lowering alleles involved in peripheral lipolysis (e.g., LPL, ANGPTL4) had no effect on liver fat but lowered risks for both type 2 diabetes and coronary artery disease.
              Article 0 comments Cited 261 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Neil M Davies: Role: research fellow
                Michael V Holmes: Role: university research lecturer
                George Davey Smith: Role: professor
                Journal
                Journal ID (nlm-ta): BMJ
                Journal ID (iso-abbrev): BMJ
                Journal ID (publisher-id): BMJ-UK
                Journal ID (hwp): bmj
                Title: The BMJ
                Publisher: BMJ Publishing Group Ltd.
                ISSN (Print): 0959-8138
                ISSN (Electronic): 1756-1833
                Publication date Collection: 2018
                Publication date (Electronic): 12 July 2018
                Volume: 362
                Electronic Location Identifier: k601
                Affiliations
                [1 ]Medical Research Council Integrative Epidemiology Unit, University of Bristol, BS8 2BN, UK
                [2 ]Population Health Sciences, Bristol Medical School, University of Bristol, Barley House, Oakfield Grove, Bristol, BS8 2BN, UK
                [3 ]Medical Research Council Population Health Research Unit, University of Oxford, UK
                [4 ]Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Richard Doll Building, Old Road Campus, Roosevelt Drive, Oxford OX3 7LF, UK.
                [5 ]National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospital, Oxford, UK
                [6 ]National Institute for Health Research Bristol Biomedical Research Centre, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK
                Author notes
                Correspondence: G Davey Smith pa-ieudirector@ 123456bristol.ac.uk
                Article
                Publisher ID: davn040667
                DOI: 10.1136/bmj.k601
                PMC ID: 6041728
                PubMed ID: 30002074
                SO-VID: 621f0525-366c-48ca-9978-b29e1bfaf88a
                Copyright © Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions
                License:

                This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/.

                History
                Date accepted : 04 December 2017
                Categories
                Subject: Research Methods & Reporting

                ScienceOpen disciplines: Medicine
                Data availability:
                ScienceOpen disciplines: Medicine

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