Heart rate variability is an important risk factor for cardiovascular disease and all-cause mortality. The acetylcholine pathway plays a key role in explaining heart rate variability in humans. We assessed whether 443 genotyped and imputed common genetic variants in eight key genes (CHAT, SLC18A3, SLC5A7, CHRNB4, CHRNA3, CHRNA, CHRM2 and ACHE) of the acetylcholine pathway were associated with variation in an established measure of heart rate variability reflecting parasympathetic control of the heart rhythm, the root mean square of successive differences (RMSSD) of normal RR intervals. The association was studied in a two stage design in individuals of European descent. First, analyses were performed in a discovery sample of four cohorts (n = 3429, discovery stage). Second, findings were replicated in three independent cohorts (n = 3311, replication stage), and finally the two stages were combined in a meta-analysis (n = 6740). RMSSD data were obtained under resting conditions. After correction for multiple testing, none of the SNPs showed an association with RMSSD. In conclusion, no common genetic variants for heart rate variability were identified in the largest and most comprehensive candidate gene study on the acetylcholine pathway to date. Future gene finding efforts for RMSSD may want to focus on hypothesis free approaches such as the genome-wide association study.

Adolescents exposed to traumatic events, including physical and sexual abuse, are at higher risk of developing problematic substance use behaviours. This study investigates associations between traumatic experiences and trajectories of substance use in adolescence and young adulthood, focusing in particular on differences in neuroendocrine and subjective stress reactivity as potential explanatory mechanisms. Using data from the TRacking Adolescents’ Individual Lives Survey (TRAILS) (N = 715), we assessed whether traumatic experiences up to age 16 were associated with differences in acute neuroendocrine stress reactivity (in terms of heart rate (HR), high-frequency heart rate variability (HF-HRV), pre-ejection period (PEP), and cortisol reactivity), as well as subjective stress reactivity, assessed in the context of a standardized stress test conducted around age 16. We then analysed whether these stress reactivity measures predicted substance use trajectories (tobacco, alcohol, and cannabis) from around age 16 to around age 22. Results showed that traumatic experiences increased the risk of following trajectories characterized by an early initiation and escalation of tobacco, alcohol, and cannabis use (vs. no use or low use trajectories). Traumatic experiences were additionally associated with a higher probability of belonging to cannabis use trajectories characterized by consistently relatively low levels of use (vs. no use) or a later escalation of use in young adulthood. Regarding mechanisms, blunted neuroendocrine stress reactivity, but not subjective stress reactivity, was inconsistently linked to trajectories of higher substance use. However, differences in acute stress reactivity did not contribute to associations between traumatic experiences and substance use trajectories, as associations between traumatic experiences and acute stress reactivity were absent. Our findings emphasize the need to explore mechanisms beyond acute stress reactivity that may explain the association between trauma and adolescent and young adult substance use.