PT  - JOURNAL ARTICLE
AU  - Alistair J. Brock
AU  - Judit García-González
AU  - Matthew O. Parker
AU  - David Jolliffe
AU  - Ari Sudwarts
AU  - Muy-Teck Teh
AU  - Elisabeth M. Busch-Nentwich
AU  - Derek L. Stemple
AU  - Adrian R. Martineau
AU  - Jaakko Kaprio
AU  - Teemu Palviainen
AU  - Valerie Kuan
AU  - Robert T. Walton
AU  - Caroline H. Brennan
TI  - Identification of <em>Slit3</em> as a locus affecting nicotine preference in zebrafish and human smoking behaviour
AID  - 10.1101/453928
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 453928
4099  - http://biorxiv.org/content/early/2019/08/30/453928.short
4100  - http://biorxiv.org/content/early/2019/08/30/453928.full
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.