RT Journal Article SR Electronic T1 Identification of Slit3 as a locus affecting nicotine preference in zebrafish and human smoking behaviour JF bioRxiv FD Cold Spring Harbor Laboratory SP 453928 DO 10.1101/453928 A1 Alistair J. Brock A1 Judit García-González A1 Matthew O. Parker A1 David Jolliffe A1 Ari Sudwarts A1 Muy-Teck Teh A1 Elisabeth M. Busch-Nentwich A1 Derek L. Stemple A1 Adrian R. Martineau A1 Jaakko Kaprio A1 Teemu Palviainen A1 Valerie Kuan A1 Robert T. Walton A1 Caroline H. Brennan YR 2019 UL http://biorxiv.org/content/early/2019/08/30/453928.abstract AB Although there is clear evidence of genetic contributions to smoking behaviour, it has proved difficult to identify causal alleles and pathways from human studies. To facilitate smoking genetics research we examined the ability of a screen of mutagenized zebrafish to predict loci affecting smoking behaviour. We identified Slit3 as a gene affecting nicotine preference in fish. Focussed SNP analysis of the homologous human locus in cohorts from UK and Finland identified two SNP variants in the SLIT3 locus that predict level of cigarette consumption and likelihood of cessation. Characterisation of Slit3 mutant larvae and adult fish revealed altered behavioural sensitivity to amisulpride, a dopaminergic and serotonergic antagonist, and increased 5htr1aa mRNA expression in mutant larvae. No effect on neuronal pathfinding was detected. These findings reveal a role for SLIT3 signalling in development of pathways affecting responses to nicotine and confirm the translational relevance of zebrafish for exploring complex human behaviours.