We investigated the effect of perception of different bitter compounds on tea, coffee and alcohol consumption in a large population-based cohort (UK Biobank) using a MR approach. Our findings showed that a higher perceived intensity of PROP and quinine decreased coffee consumption and that a higher perceived intensity of caffeine increased coffee consumption; opposite relationships were observed for tea consumption. For alcohol, a higher predicted intensity of PROP resulted in lower consumption but the perception of quinine and caffeine had no clear influence.

Increased predicted perceived intensity of PROP and quinine leads to a lower coffee intake and a lower risk of being a heavy coffee drinker. The direction of association could be attributed to the inborn aversion towards bitterness, which is a defensive mechanism that prevents ingestion of poisonous food44. Previous studies investigating the effect of PROP taster status on coffee consumption have reported null findings12,13,17,18,22 (except for one study of Polish elderly women (n = 118) showed that tasters consume coffee more frequently)16, but with sample sizes between 8 and 3328, these studies may have been underpowered. In the current analysis of over 438,870 cohort participants, the TAS2R38 genotype corresponding to increased perceived PROP intensity was associated with a lower consumption of coffee. The effect size is notably small, thus warranting a large sample size to detect. For the association with the perception of quinine, our finding can be supported by an earlier report that coffee drinkers tend to be less sensitive to quinine15. The effect of quinine on coffee is stronger than that of PROP, presumably because the quinine naturally occurs in coffee45 whereas PROP does not.

While the perception of caffeine demonstrated the largest magnitude of association, its direction of effect was opposite to the other two bitter substances PROP and quinine, i.e. an increased predicted perceived intensity of caffeine leads to a higher intake of coffee. Caffeine is a non-volatile component of coffee and it contributes to the perceived strength, body and bitterness of coffee46, which has been related to its intake11,15. It is possible that coffee consumers acquire a taste for (or an ability to detect) caffeine given the learned positive reinforcement (i.e. stimulation) elicited by caffeine.

For the relationship between bitter taste perception and tea intake, we showed that a higher predicted perceived intensity of PROP and quinine increased tea intake and a higher predicted perceived intensity of caffeine decreased intake. These effects of bitter taste on tea consumption were in the opposite direction compared with those on coffee consumption, consistent with the negative correlation between coffee and tea intake in the UK Biobank cohort. A negative relationship of similar magnitude has also been reported in an Australian population (N = 3908)47. Nevertheless, our sensitivity analyses, which used the IV estimate on tea conditional on coffee (and vice versa), showed the same direction of association and revealed a robust association between tea intake and the perception of PROP and caffeine (and between coffee intake and the perception of quinine and caffeine).

For alcohol, our MR results indicated that increased predicted perceived intensity of PROP led to a lower intake of alcohol. It has been reported that alcohol elicits bitterness in humans48,49 and such bitter sensation can mediate consumption behaviour50. Findings from this study could be supported by previous observations that a higher perceived intensity of PROP is associated with a stronger perceived intensity of alcohol and a lower intake14,19,50,51. While inconsistencies have been reported between sexes14,16,19, here we found no strong evidence of a difference between males and females in the large UK Biobank cohort.

The strengths of our study include the use of a two-sample approach in MR to avoid biased estimates40. Given that each of these SNPs are functionally related to taste biology, each of the SNP used were strong instruments backed with statistical evidence as well as biological plausibility. Taste perception can change overtime, whereas MR analyses evaluate the impact of average differences in taste perception across the life course on bitter beverage consumption. Thus, if there were a sensitive period for the impact (e.g. if bitter taste perception in early childhood determined drinking habits that persisted into later life) our results would be an underestimate of that effect. Additionally, the use of per SD change in taste perception allows us to assess the effect of changing from perception scale of strong/moderate to moderate/weak, without worrying about within-individual variation in taste perception as observed in earlier test-retest validations52. The use of a mixed model approach also allows us to leverage the relatedness in the UKB cohort to gain higher statistical power, resulting in slightly narrower confidence intervals than conventional regression models that exclude related individuals (Supplementary Table 11). Although our choice of a cut-off for high coffee and tea drinkers is arbitrary (based on a percentile), adopting alternative cut-offs made no meaningful difference to the results (Supplementary Table 12).

A major limitation for our study is the relatively small sample size (n = 1757) used to estimate the SNP-bitter taste associations. However, this limitation is unlikely to have substantially biased our finding as all of the SNPs used in this study have been replicated in other independent GWAS26,35. As our experiments only consist of one genetic instrument per trait, we were unable to perform sensitivity analyses that explore the validity of IVs through multiple SNPs-based approaches (e.g. MR-Egger40 and weighted median53 analyses) to evaluate potential bias due to horizontal pleiotropy and therefore we could not exclude the possibility that the SNPs are associated with bitter beverage intake via independent pathways. However, given the functional role of these SNPs in bitter taste receptor genes27 and the evidence showing the association of the expression of bitter taste receptor (i.e. TAS2R38) with bitter taste perception and intake of caffeine54, these SNPs are more likely to act on the intake of bitter beverage via taste perception. Applying multiple instruments for each trait can potentially allow better assessment of pleiotropy through the use of statistical models, although this will unlikely translate to better precision on our causal estimates given our individual SNP instruments already explain reasonably high amount of variance on bitter tastes. Additionally, our pleiotropic tests using publicly available GWAS summary results did not show evidence of effect of these SNPs on potential confounders (Supplementary Tables 13 and 14). Nevertheless, further research is still required to validate the causal effects detected in the present study.

The response amongst those invited to UK Biobank was ~5% and participants differ considerably from the underlying population with respect to socioeconomic position, health and survival55. This could potentially introduce some level of selection bias influencing our MR associations56. For example, if non-responsiveness is related to genetic predictors of a number of mental health and lifestyle/behavioural outcomes which happen to also confound drinking behaviour57. However, sensitivity analyses (Supplementary Table 13) evaluating the association between these bitter taste SNPs and proxies of socio-economic status (i.e. UK Biobank townsend deprivation index and number of vehicle in household) found no evidence of association. It is possible that behavioural and disease traits correlated to coffee consumption (e.g. diet behaviour, smoking, anorexia, and insomnia) influence bitter taste perception. But using publicly available GWAS summary data42,43 we found no strong evidence for this (Supplementary Table 14).

The use of the wald-type estimator to evaluate the causal effect has an intrinsic assumption that the exposure-outcome relationship is linear. For behavioural traits like coffee consumption, this assumption can be violated when we assess the effect of bitter taste on individuals at the extreme end of the trait distribution (i.e. non-tasters, or extremely sensitive tasters). We examined associations both as continuous and binary traits, in general the inference drawn for the continuous measure (e.g. cups per day) was similar to those estimated on drinker status.

Finally, beverage consumption data in the UK Biobank were based on self-reporting which will inevitably contain recall bias and measurement error, but these are unlikely to have inflated Type I error rates in MR analyses. Our findings were based on the intake of black and green tea, and the effects may differ for other tea types with different taste profiles. It is also important to note that our findings do not necessarily generalise to non-European populations.

Overall, our findings demonstrate that differences in bitter taste perception are causally associated with specific bitter beverage consumption behaviour. The magnitudes of causal effects that we see for coffee and tea are small (i.e. 0.02 to 0.15 cups per day for a SD greater bitter taste perception). Given the popularity of these bitter beverages at a population level their consumption could have significant impact on health outcomes, but this requires further investigation.