Thus, it is not unreasonable to propose that the association reported in this study reflect genotype-specific transcriptional activity of the PIK3R1 gene. Alternatively, the genetic variation SP600125 mediating the association might affect splicing of the PI3KR1 transcript, or expression of associated regulatory non-coding RNAs. Taken together, our results indicate that AbMole BioScience kinase inhibitors variations in the PIK3R1 gene are associated with multiple aspects of alcohol risk drinking behaviour in male adolescents, suggesting a relevance of PIK3R1 genotypes for early onset of alcoholism in humans. It is noteworthy that the adolescents in our study had their first drink at age 13.23 +/2 1.05 years on average when assessed for alcohol consumption at age 15, an age which might be too early for complete development of risky alcohol drinking behaviour. Follow up studies including drinking behaviour of these individuals later in adolescence and early adulthood will be of great interest to fully assess drinking behaviour. As environmental components like parental substance use, parenting practice and peer influence might play a significant role in the development of alcohol use disorders, inclusion of these informations as covariables in those studies will help monitor possible gene6environment interactions. In addition, a limitation of our work is its relatively small sample size, which prevents powerful statistical analysis. Experiments involving the replication of our findings in other populations, identification and characterisation of the functional variants conferring risk of alcohol misuse will have to be carried out to definitely gauge how alterations in PI3KR1 impacts alcohol response-related behaviours. receptors and by coupling group I mGluRs to translation initiation. Thus, a role for PI3K in alcoholism might be inferred from its involvement in the glutamatergic transmission. Besides, a role for PI3K in addiction is further suggested by its role in neurotrophin-mediated potentiation and transmitter release. This hypothesis is supported by a recent study showing association of antisocial alcohol dependence with SNPs within the human neurotrophin receptor TrkB gene. Our SNP analysis was limited to the regulatory regions of the gene, including exon-intron boundaries and led to the identification of a previously unknown SNP. The functional impact of these SNPs on PIK3R1 regulation and activity is not known, however hypothesis as to the molecular mechanisms that could mediate their effect can be generated. For example, htSNP4 and most of the SNPs in its vicinity alter putative binding sites of transcription factors that might influence transcriptional activity of this gene. Specifically, SNP8 which is in strong linkage disequilibrium with SNP4 creates a canonical E-box, binding site for basic helix-loophelix transcriptional regulators. Members of this family of transcription factors play key roles in the development of organisms ranging from yeast to humans. Several are widely expressed, while others including the neurogenin subfamily that play an important role in neurogenesis show a tissue-restricted pattern. Regulatory elements that significantly contribute to gene expression are present in intronic regions of several genes, including the human serotonin transporter gene. Thus, it is not unreasonable to propose that the association reported in this study reflect genotype-specific transcriptional activity of the PIK3R1 gene. Alternatively, the genetic variation mediating the association might affect splicing of the PI3KR1 transcript, or expression of associated regulatory non-coding RNAs. Taken together, our results indicate that variations in the PIK3R1 gene are associated with multiple aspects of alcohol risk drinking behaviour in male adolescents, suggesting a relevance of PIK3R1 genotypes for early onset of alcoholism in humans. It is noteworthy that the adolescents in our study had their first drink at age 13.23 +/2 1.05 years on average when assessed for alcohol consumption at age 15, an age which might be too early for complete development of risky alcohol drinking behaviour. Follow up studies including drinking behaviour of these individuals later in adolescence and early adulthood will be of great interest to fully assess drinking behaviour.