Abstract
To facilitate smoking genetics research we determined whether a screen of mutagenized zebrafish for nicotine preference could predict loci affecting smoking behaviour. From 30 screened F3 sibling groups, where each was derived from an individual ethyl-nitrosurea mutagenized F0 fish, two showed increased or decreased nicotine preference. Out of 25 inactivating mutations carried by the F3 fish, one in the slit3 gene segregated with increased nicotine preference in heterozygous individuals. Focussed SNP analysis of the human SLIT3 locus in cohorts from UK (n=863) and Finland (n=1715) identified two variants associated with cigarette consumption and likelihood of cessation. Characterisation of slit3 mutant larvae and adult fish revealed decreased sensitivity to the dopaminergic and serotonergic antagonist amisulpride, known to affect startle reflex that is correlated with addiction in humans, and increased htr1aa mRNA expression in mutant larvae. No effect on neuronal pathfinding was detected. These findings reveal a role for SLIT3 in development of pathways affecting responses to nicotine in zebrafish and smoking in humans.
Highlights
Tobacco smoking is the leading preventable cause of death worldwide placing a heavy social and financial burden on society (World Health Organization, 2017; National Center for Chronic Disease Prevention and Health Promotion (US) Office on Smoking and Health, 2014; Xu et al, 2015)
Among 30 mutant zebrafish families screened for Conditioned place preference (CPP), we identified one family showing increased nicotine preference compared to wild types
Out of the 13 pre-identified loss-of-function mutations in that family, only one in the slit3 gene co-segregated with the behaviour
Summary
Tobacco smoking is the leading preventable cause of death worldwide placing a heavy social and financial burden on society (World Health Organization, 2017; National Center for Chronic Disease Prevention and Health Promotion (US) Office on Smoking and Health, 2014; Xu et al, 2015). It is well established that aspects of smoking behaviour have a strong genetic component (Munafoet al., 2004; Batra et al, 2003; Liu et al, 2019; Erzurumluoglu et al, 2019). Identifying causal genetic factors and exploring the mechanisms by which they act is challenging in human studies: the field has been characterized by small effect sizes and lack of replication such that. The strongest evidence for causal effects is for functional variants in CHRNA5 (Chen et al, 2015) and CYP2A6 (Munafoet al., 2004) affecting amount smoked and nicotine metabolism, respectively. Recent large studies have identified numerous new association loci, but their significance is yet to be biologically characterised (Liu et al, 2019; Erzurumluoglu et al, 2019)
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