Incorporating biological and clinical insights into variant choice for Mendelian randomisation: examples and principles
Mendelian randomisation is an accessible and valuable epidemiological approach to provide insight into the causal nature of relationships between risk factor exposures and disease outcomes. However, if performed without critical thought, we may simply have replaced one set of implausible assumptions...
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BMJ Publishing Group
2024-02-01
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| Series: | eGastroenterology |
| Online Access: | https://egastroenterology.bmj.com/content/2/1/e100042.full |
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| author | Stephen Burgess Héléne Toinét Cronjé |
| author_facet | Stephen Burgess Héléne Toinét Cronjé |
| author_sort | Stephen Burgess |
| collection | DOAJ |
| description | Mendelian randomisation is an accessible and valuable epidemiological approach to provide insight into the causal nature of relationships between risk factor exposures and disease outcomes. However, if performed without critical thought, we may simply have replaced one set of implausible assumptions (no unmeasured confounding or reverse causation) with another set of implausible assumptions (no pleiotropy or other instrument invalidity). The most critical decision to avoid pleiotropy is which genetic variants to use as instrumental variables. Two broad strategies for instrument selection are a biologically motivated strategy and a genome-wide strategy; in general, a biologically motivated strategy is preferred. In this review, we discuss various ways of implementing a biologically motivated selection strategy: using variants in a coding gene region for the exposure or a gene region that encodes a regulator of exposure levels, using a positive control variable and using a biomarker as the exposure rather than its behavioural proxy. In some cases, a genome-wide analysis can provide important complementary evidence, even when its reliability is questionable. In other cases, a biologically-motivated analysis may not be possible. The choice of genetic variants must be informed by biological and functional considerations where possible, requiring collaboration to combine biological and clinical insights with appropriate statistical methodology. |
| format | Article |
| id | doaj-art-3aa5fc423ed54ed2afd1022499a63af6 |
| institution | Kabale University |
| issn | 2766-0125 2976-7296 |
| language | English |
| publishDate | 2024-02-01 |
| publisher | BMJ Publishing Group |
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| series | eGastroenterology |
| spelling | doaj-art-3aa5fc423ed54ed2afd1022499a63af62024-12-25T15:50:13ZengBMJ Publishing GroupeGastroenterology2766-01252976-72962024-02-012110.1136/egastro-2023-100042Incorporating biological and clinical insights into variant choice for Mendelian randomisation: examples and principlesStephen Burgess0Héléne Toinét Cronjé12 Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK3 Health Analytics, Lane Clark & Peacock LLP, London, UKMendelian randomisation is an accessible and valuable epidemiological approach to provide insight into the causal nature of relationships between risk factor exposures and disease outcomes. However, if performed without critical thought, we may simply have replaced one set of implausible assumptions (no unmeasured confounding or reverse causation) with another set of implausible assumptions (no pleiotropy or other instrument invalidity). The most critical decision to avoid pleiotropy is which genetic variants to use as instrumental variables. Two broad strategies for instrument selection are a biologically motivated strategy and a genome-wide strategy; in general, a biologically motivated strategy is preferred. In this review, we discuss various ways of implementing a biologically motivated selection strategy: using variants in a coding gene region for the exposure or a gene region that encodes a regulator of exposure levels, using a positive control variable and using a biomarker as the exposure rather than its behavioural proxy. In some cases, a genome-wide analysis can provide important complementary evidence, even when its reliability is questionable. In other cases, a biologically-motivated analysis may not be possible. The choice of genetic variants must be informed by biological and functional considerations where possible, requiring collaboration to combine biological and clinical insights with appropriate statistical methodology.https://egastroenterology.bmj.com/content/2/1/e100042.full |
| spellingShingle | Stephen Burgess Héléne Toinét Cronjé Incorporating biological and clinical insights into variant choice for Mendelian randomisation: examples and principles eGastroenterology |
| title | Incorporating biological and clinical insights into variant choice for Mendelian randomisation: examples and principles |
| title_full | Incorporating biological and clinical insights into variant choice for Mendelian randomisation: examples and principles |
| title_fullStr | Incorporating biological and clinical insights into variant choice for Mendelian randomisation: examples and principles |
| title_full_unstemmed | Incorporating biological and clinical insights into variant choice for Mendelian randomisation: examples and principles |
| title_short | Incorporating biological and clinical insights into variant choice for Mendelian randomisation: examples and principles |
| title_sort | incorporating biological and clinical insights into variant choice for mendelian randomisation examples and principles |
| url | https://egastroenterology.bmj.com/content/2/1/e100042.full |
| work_keys_str_mv | AT stephenburgess incorporatingbiologicalandclinicalinsightsintovariantchoiceformendelianrandomisationexamplesandprinciples AT helenetoinetcronje incorporatingbiologicalandclinicalinsightsintovariantchoiceformendelianrandomisationexamplesandprinciples |