We conducted a genome-wide gene × environment interaction analysis to identify genetic variants that interact with cannabis dependence (CaD) in influencing risky sexual behaviours (RSB). Methods: Our sample included cannabis-exposed and sexually experienced African-American and European-American participants. A DSM-IV CaD diagnosis and RSB were evaluated using the Semi-Structured Assessment for Drug Dependence and Alcoholism. We analyzed RSBs as a score that takes into account experiences of

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... rotected sex and multiple sexual partners. Results: A total of 3350 people participated in our study; 43% had a CaD diagnosis, 56% were African-American and 33% were women. We identified a genome-wide significant locus in African-American participants (S100A10 rs72993629, p = 2.73 × 10 -8 ) and a potential transpopulation signal in women (CLTC rs12944716, p = 5.27 × 10 -8 ). A resting-state fMRI follow-up analysis of S100A10 rs72993629 conducted in an independent cohort showed 2 significant associations: reduced power of the left paracentral lobule in amplitude of low frequency fluctuations (ALFF) analysis (p = 7.8 × 10 -3 ) and reduced power of the right pallidum in fractional ALFF analysis (p = 4.6 × 10 -3 ). The activity of these brain regions is known to be involved in sexual functions and behaviours. The S100A10 result functionally recapitulated our S100B finding observed in our previous genome-wide association study of CaD. The probability of identifying 2 S100 genes in 2 independent genome-wide investigations by chance is approximately 1 in 1.1 million. Limitations: We were not able to identify any African-American cohort with appropriate sample size, and phenotypic assessment is available to replicate our findings. Conclusion: The S100A10 and S100B genes, which are located on different chromosomes, encode specialized calcium-binding proteins. These data support a role for calcium homeostasis in individuals with CaD and its induced behaviours. S100A10 identified in a genome-wide gene × CaD interaction analysis of RSB J Psychiatry Neurosci 2017;42(4)