Resting heart rate and antisocial behaviour: a Mendelian randomisation study

www.nature.com/scientificreports OPEN Resting heart rate and antisocial behaviour: a Mendelian randomisation study Lucy Karwatowska 1*, Leonard Frach 2, Tabea Schoeler 3, Jorim J. Tielbeek Joseph Murray 5,6, Eco de Geus 7, Essi Viding 8 & Jean‑Baptiste Pingault 2,9 4 , Observational studies frequently report phenotypic associations between low resting heart rate (RHR) and higher levels of antisocial behaviour (ASB), although it remains unclear whether this relationship reflects causality. To triangulate evidence, we conducted two-sample univariable Mendelian randomisation (MR), multivariable MR and linkage disequilibrium score regression (LDSC) analyses. Genetic data were accessed from published genome-wide association studies (GWAS) for RHR (n = 458,835) and ASB (n = 85,359) for the univariable analyses, along with a third GWAS for heart rate variability (HRV; n = 53,174) for all other analyses. Genome-wide significant (p < 5 × 10−8) singlenucleotide polymorphisms associated with RHR (n = 278) were selected as instrumental variables and the outcome was a composite measure of ASB. No causal association was observed between RHR and ASB (BIVW =  − 0.0004, p = 0.841). The multivariable MR analyses including RHR and HRV also suggested no causal associations (BIVW = 0.016, p = 0.914) and no genetic correlations between the heart rate measures and ASB were observed using LDSC (rg = 0.057, p = 0.169). Sensitivity analyses suggested that our results are not likely to be affected by heterogeneity, pleiotropic effects, or reverse causation. These findings suggest that individual differences in autonomic nervous system functioning indexed by RHR are not likely to directly contribute to the development of ASB. Therefore, previously observed associations between RHR and ASB may arise from confounding, reverse causation, and/or additional study characteristics. Further causally informative longitudinal research is required to confirm our findings, and caution should be applied when using measures of RHR in interventions targeting ASB. Antisocial behaviour (ASB), which includes aggression, rule-breaking and acts of violence, imposes a substantial economic and social burden on the individual, their community and wider society. Individuals who display high levels of ASB are at risk of lifelong adverse outcomes, such as poor mental health, substance misuse, criminal behaviour and u nemployment1–4. Furthermore, up to half of individuals who display ASB in childhood continue to exhibit these behaviours through adolescence and a dulthood5–7. Considering these long-term and pervasive adverse outcomes, it is important to understand the aetiology of ASB to inform early identification and evidencebased intervention efforts. Numerous reviews exist on putative risk factors for ASB, which include environmental and neurobiological factors8–11. Physiological markers, such as those indexing autonomic nervous system (ANS) activity, are particularly important in elucidating potential mechanisms underlying the development of A SB12,13. Of these, resting heart rate (RHR), defined as the number of heart beats per minute while at rest, is the most well-studied. Observational studies frequently report a strong inverse relationship between RHR and ASB, where individuals with lower RHR display higher levels of various types of ASB, including child conduct problems, juvenile delinquency and adult v iolence14–19. Several meta-analyses have been conducted on this t opic20–23, all reporting 1 Great Ormond Street Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK. 2Department of Clinical, Educational and Health Psychology, University College London, London, UK. 3Department of Computational Biology, University of Lausanne, Lausanne, Switzerland. 4Department of Complex Trait Genomics, VU University Amsterdam, Amsterdam, The Netherlands. 5Postgraduate Program in Epidemiology, Federal University of Pelotas, Pelotas, Brazil. 6Human Development and Violence Research Centre, Federal University of Pelotas, Pelotas, Brazil. 7Department of Biological Psychology, Amsterdam Public Health Research Institute, Amsterdam, The Netherlands. 8Developmental Risk & Resilience Unit, Division of Psychology & Language Sciences, University College London, London, UK. 9Social, Genetic, and Developmental Psychiatry, King’s College London, De Crespigny Park, London, UK. *email: Scientific Reports | (2023) 13:10212 | https://doi.org/10.1038/s41598-023-37123-y 1 Vol.:(0123456789) www.nature.com/scientificreports/ a robust association between the two traits, with one review stating that “resting heart rate is a possible causal risk factor for antisocial behavior”20. Various potential mechanisms have been proposed to explain the relationship between RHR and ASB. The two main theories are the f earlessness24 and sensation-seeking h ypotheses25. According to the fearlessness hypothesis, an individual with a low RHR has a higher threshold for experiencing fear than individuals with higher RHRs, partly due to attenuated ANS responses to aversive stimuli. The typical links between poor behavioural choices (e.g., aggression) and aversive stimuli (e.g., perceived punishment cues) are either not established or are insufficiently established in individuals with lower RHR. As such, an individual with lower RHR would have inappropriately low expectations of negative outcomes and be prone to repeat poor decision making. In support of this hypothesis, many behavioural experiments report that participants who show deficient fear conditioning and reduced anticipatory fear reactivity have lower RHRs and higher levels of A SB26,27. The sensation-seeking hypothesis states that individuals with lower RHR have low basal ANS activity and are chronically hypo-aroused. Hypo-arousal is an unpleasant physiological state and therefore individuals with lower RHR seek to increase their arousal to a normal level by engaging in ASB. Sensation-seeking has been shown to be associated with both RHR and ASB, with some evidence suggesting that sensation-seeking is a mediator between these two f actors28–30. Although the link between RHR and ASB is well studied, questions remain over whether these two phenotypes are causally related. This is in part due to limitations in the existing literature which prevent the drawing of causal conclusions. A closer look at the studies included in the four meta-analyses20–23 shows that the majority of studies have used small and/or selective samples, which can produce unreliable and ungeneralisable estimates. In recent years, authors have attempted to include larger, unselected samples followed up over time. The findings from these studies are more inconsistent than those from earlier studies reporting a strong negative relationship between RHR and ASB, with some more recent studies confirming earlier findings28,31–33 and others suggesting no relationship between these two f actors12, (...truncated)