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.

Early life stress has been shown to contribute to alterations in biobehavioral regulation. Genetic make-up, especially related to social sensitivity, might affect the child’s vulnerability to these alterations. This study examined whether maternal verbally aggressive behavior in early infancy interacts with oxytocin polymorphisms in changing resting cardiovascular outcomes at age 5–6. In the Amsterdam-Born-Children-and-their-Development-(ABCD)-study, a large prospective, observational, population-based birth cohort, maternal verbally aggressive behavior was assessed in the 13th postnatal week (range 11–25 weeks, SD 2 weeks) by a questionnaire (maternal self-report). Indicators of resting cardiac autonomic nervous system activity (sympathetic drive by pre-ejection period, parasympathetic drive by respiratory sinus arrhythmia), heart rate, and blood pressure were measured at age 5–6 years. Data on oxytocin receptor gene polymorphisms rs53576, rs2268498 and oxytocin polymorphisms rs2740210, rs4813627, were collected (N = 966 included). If the child was carrier of the rs53576 GG variant, exposure to maternal verbally aggressive behavior (10.6%) was associated with increased systolic blood pressure at age 5–6 (B = 4.9 mmHg,95% CI[2.2;7.7]). If the child was carrier of the rs2268498 TT/TC variant, exposure to maternal verbally aggressive behavior was associated with increased systolic blood pressure at age 5–6 (B = 3.0 mmHg,95%CI[1.0:5.0]). No significant interactions of maternal verbally aggressive behavior with oxytocin gene polymorphisms on heart rate or cardiac autonomic nervous system activity were found. In conclusion, oxytocin receptor gene polymorphisms may partly determine a child’s vulnerability to develop increased systolic blood pressure after being exposed to maternal verbally aggressive behavior in early infancy.