Abstract
BackgroundSlow 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.MethodsBrain-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.FindingsIn 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.InterpretationGender-dependant slow neurotransmission may convey both genetic and environmental vulnerabilities selectively to SUDs.FundingGrants 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).
Highlights
Substance abuse is the second leading cause of chronic diseases worldwide [1,2] but most of the substance use disorders (SUDs), including alcohol use disorder (AUD), still lack effective medications [3], warranting a better understanding of the disease mechanisms
The findings consistently suggest that both PPP1R12B and PPP1R1B cell type- influence a selected vulnerability to develop SUDs in a gender-dependant manner and that epistatic mechanisms may uncover missing heritability alternatively sought for complex disorders [21]
Distinct cellular expression of Ppp1r12b was found in medial parietal association area (M/PtA), ventral tegmental area (VTA), and medial prefrontal cortex (mPFC) neurons, while diffuse expression was found in CPU and lateral habenular nucleus (LHb) (SNc was similar to VTA with a distinct cellular pattern; central nucleus of the amygdala (CeA) and nucleus accumbens (NAc) were similar to diffuse CPU; hippocampus had a pattern in between mPFC and LHb, data not shown)
Summary
Substance abuse is the second leading cause of chronic diseases (behind hypertension) worldwide [1,2] but most of the substance use disorders (SUDs), including alcohol use disorder (AUD), still lack effective medications [3], warranting a better understanding of the disease mechanisms. In humans with polysubstance abuse, meta-analysis of pre-existing datasets revealed that PPP1R12B and PPP1R1B, 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
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