Exploring pleiotropy in Mendelian randomisation analyses: What are genetic variants associated with “cigarette smoking initiation” really capturing?

Abstract

AbstractBackgroundGenetic variants used as instruments for exposures in Mendelian randomisation (MR) analyses may also 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 to which horizontal pleiotropy may be present, using smoking behaviours as an example.MethodsWe first ran a phenome-wide association study in UK Biobank, using a genetic instrument for smoking initiation. From the most strongly associated phenotypes, we selected those that we considered could either plausibly or not plausibly be caused by smoking. We next examined the association between genetic instruments for smoking initiation, smoking heaviness and lifetime smoking and these phenotypes in both UK Biobank and the Avon Longitudinal Study of Parents and Children (ALSPAC). We conducted negative control analyses among never smokers, including children in ALSPAC.ResultsWe found evidence that smoking-related genetic instruments (mainly for smoking initiation and lifetime smoking) were associated with phenotypes not plausibly caused by smoking in UK Biobank and (to a lesser extent) ALSPAC, although this may reflect the much smaller sample size in ALSPAC. We also observed associations with several phenotypes among never smokers.ConclusionOur results suggest that genetic instruments for smoking-related phenotypes demonstrate horizontal pleiotropy. When using genetic variants – particularly those for complex behavioural exposures – in genetically-informed causal inference analyses (e.g., MR) it is important to include negative control outcomes where possible, and other triangulation approaches, to avoid arriving at incorrect conclusions.