Exploring pleiotropy in Mendelian randomisation analyses: What are genetic variants associated with ‘cigarette smoking initiation’ really capturing?
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Le résumé fourni par la source
Genetic variants used as instruments for exposures in Mendelian randomisation (MR) analyses may have horizontal pleiotropic effects (i.e., influence outcomes via pathways other than through the exposure), which can undermine the validity of results. We examined the extent of this using smoking behaviours as an example. We first ran a phenome-wide association study in UK Biobank, using a smoking initiation genetic instrument. From the most strongly associated phenotypes, we selected those we considered could either plausibly or not plausibly be caused by smoking. We examined associations between genetic instruments for smoking initiation, smoking heaviness and lifetime smoking and these phenotypes in UK Biobank and the Avon Longitudinal Study of Parents and Children (ALSPAC). We conducted negative control analyses among never smokers, including children. We found evidence that smoking-related genetic instruments were associated with phenotypes not plausibly caused by smoking in UK Biobank and (to a lesser extent) ALSPAC. We observed associations with phenotypes among never smokers. Our results demonstrate that smoking-related genetic risk scores are associated with unexpected phenotypes that are less plausibly downstream of smoking. This may reflect horizontal pleiotropy in these genetic risk scores, and we would encourage researchers to exercise caution this when using these and genetic risk scores for other complex behavioural exposures. We outline approaches that could be taken to consider this and overcome issues caused by potential horizontal pleiotropy, for example, in genetically informed causal inference analyses (e.g., MR) it is important to consider negative control outcomes and triangulation approaches, to avoid arriving at incorrect conclusions.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Exploring pleiotropy in Mendelian randomisation analyses: What are genetic variants associated with ‘cigarette smoking initiation’ really capturing?
- Date Crossref
- 04/08/2024
- Éditeur
- Wiley
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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University of Bristol MRC Integrative Epidemiology Unit pays non établi dans la noticeUniversité ou école supérieure
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Lovisenberg Diakonale Høgskole pays non établi dans la noticeUniversité ou école supérieure
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University Hospitals Bristol NHS Foundation Trust National Institute for Health Research Bristol Biomedical Research Centre pays non établi dans la noticeÉtablissement de santé
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National Institute for Health and Care Research pays non établi dans la noticeOrganisme public
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School of Psychological Science pays non établi dans la noticeUniversité ou école supérieure
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Nic Waals Institute pays non établi dans la noticeStructure de recherche
MRC Integrative Epidemiology Unit — University of Bristol, Lovisenberg Diakonale Høgskole et National Institute for Health Research Bristol Biomedical Research Centre — University Hospitals Bristol NHS Foundation Trust, avec 3 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.