LAUSR

Background Synaptotagmin 1 is expressed in synaptic vesicles and plays an important role on neuroexocytosis. A variant in its encoding gene (SYT1-rs2251214) has been associated with ADHD susceptibility and with other externalizing behaviors and comorbidities. Recently, it was also shown to influence response variability to Methylphenidate (MPH) in adults with ADHD, being associated with both short and long term treatment response and persistence, as well as other outcomes. Although the stimulant effects of MPH and cocaine are similar and seem to be mediated by inhibition of dopamine reuptake, additional mechanisms related to increases in the release of neurotransmitters might also be involved in the action of these stimulants. This study aims to investigate if this genetic variation in the exocytosis-related gene SYT1 would also have an influence in crack cocaine addiction susceptibility and its severity. A pathway study evaluating genes related to neurotransmitter release have already described a nominal association of other SYT1 variant with cocaine dependence. Methods Three hundred and fifteen crack cocaine users (47.6% are women) and seven hundred and sixty-nine controls (43.4% are women) were enrolled in this study. All participants are white Brazilians of European descent. Diagnoses and clinical assessments were performed according to the DSM-IV criteria. The Addiction Severity Index 6th version was used to assess the severity of dependence. Logistic regression models, general linear models and generalized estimating equations were used to evaluate the effects of the SYT1-rs2251214 SNP on the outcomes investigated. Results A significant effect of the SYT1-rs2251214 SNP on crack cocaine addiction susceptibility was found (P=0.011), where the GG genotype confers risk to crack cocaine addiction. Effects were analyzed separately according to sex, where it was associated in women (P=0.022), but not in men (P=0.177). Crack cocaine addicted women presenting this genotype had significantly lower scores on severity indexes regarding family/social problems (P=0.016) and psychiatric problems (P=0.042). Furthermore, these women seem to have experimented crack cocaine earlier than those carrying the A-allele (P=0.024). Discussion The findings that women with SYT1-rs2251214 GG genotype have increased susceptibility to crack cocaine addiction and experiment this substance earlier are in accordance with a previous report showing a more externalizing profile associated with this genotype. On the other hand, the A-allele related higher severity scores might reflect a “stronger response” to crack cocaine use, paralleling the A-allele reported better response to MPH treatment. That is, the presence of the A-allele might be related to the pharmacodynamics of different stimulants, even if with opposite effects in relation to the susceptibility to both ADHD and crack cocaine addiction. These SYT1-rs2251214 SNP effects reinforce the importance of this gene in psychiatric genetics, and further suggest that the present results should be replicated in independent samples.