BACKGROUND: Slow neurotransmission including DARPP-32 signalling is implicated in substance use disorders (SUDs) by experimental systems but not yet in the human aetiology. PPP1R12B, encoding another protein in the DARPP-32 family, hasn't been studied in the brain. METHODS: Brain-regional gene activity was assessed in three different animal models of SUDs for mRNA level alterations. Genetic associations were assessed by meta-analysis of pre-existing dbGaP GWAS datasets for main effects and epistasis with known genetic risks, followed by cell type-specific pathway delineation. Parkinson's disease (PD) was included as a dopamine-related disease control for SUDs. FINDINGS: In animal models of SUDs, environmentally-altered PPP1R12B expression sex-dependently involves motivation-related brain regions. In humans with polysubstance abuse, meta-analysis of pre-existing datasets revealed that PPP1R12B and PPP1R1B, although expressed in dopamine vs. dopamine-recipient neurons, exerted similar interactions with known genetic risks such as ACTR1B and DRD2 in men but with ADH1B, HGFAC and DRD3 in women. These interactions reached genome-wide significances (Pmeta<10-20) for SUDs but not for PD (disease selectivity: P = 4.8 × 10-142, OR = 6.7 for PPP1R12B; P = 8.0 × 10-8, OR = 2.1 for PPP1R1B). CADM2 was the common risk in the molecular signalling regardless of gender and cell type. INTERPRETATION: Gender-dependant slow neurotransmission may convey both genetic and environmental vulnerabilities selectively to SUDs. FUNDING: Grants from National Institute on Drug Abuse (NIDA) and National Institute on Alcohol Abuse and Alcoholism (NIAAA) of U.S.A. and National Natural Science Foundation of China (NSFC).

• Keywords
• Adolescence, Cell type-specific, Environmental risk, Missing heritability, Polysubstance abuse, Slow neurotransmission,
• MeSH
• Genome-Wide Association Study MeSH
• Dopamine and cAMP-Regulated Phosphoprotein 32 genetics   metabolism   MeSH
• Epistasis, Genetic * MeSH
• Genetic Heterogeneity MeSH
• Genetic Predisposition to Disease MeSH
• Gene Regulatory Networks MeSH
• Rats MeSH
• Humans MeSH
• Disease Models, Animal MeSH
• Brain metabolism   pathology   MeSH
• Mice MeSH
• Disease Susceptibility MeSH
• Synaptic Transmission genetics   MeSH
• Organ Specificity genetics   MeSH
• Substance-Related Disorders diagnosis   etiology   metabolism   MeSH
• Protein Phosphatase 1 genetics   metabolism   MeSH
• Gene Expression Regulation MeSH
• Sex Factors MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Dopamine and cAMP-Regulated Phosphoprotein 32 MeSH
• PPP1R12B protein, human MeSH Browser
• PPP1R1B protein, human MeSH Browser
• Protein Phosphatase 1 MeSH