Dataset Information

Epistatic evidence for gender-dependant slow neurotransmission signalling in substance use disorders: PPP1R12B versus PPP1R1B.

ABSTRACT: 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).

SUBMITTER: Liu K

PROVIDER: S-EPMC7581882 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Epistatic evidence for gender-dependant slow neurotransmission signalling in substance use disorders: PPP1R12B versus PPP1R1B.

Liu Kefu K Zhao Juan J Chen Chunnuan C Xu Jie J Bell Richard L RL Hall Frank S FS Koob George F GF Volkow Nora D ND Qing Hong H Lin Zhicheng Z

EBioMedicine 20201021

<h4>Background</h4>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.<h4>Methods</h4>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 effe ...[more]

PMID: 33096475

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Project description:BackgroundAlcohol and other drug use disorders contribute substantially to the global burden of illness. The majority of people with substance use disorders do not receive any treatment for their problems, and developing treatments that are attractive and effective to patients should be a priority. However, whether treatment is best delivered in a group format or an individual format has only been studied to a very limited degree. The COMDAT (Combined Drug and Alcohol Treatment) trial evaluates the feasibility, acceptability, and cost effectiveness of MOVE group (MOVE-G) treatment versus MOVE individual (MOVE-I) treatment in four community-based outpatient treatment centres in Denmark.MethodsA two-arm non-inferiority trial comparing MOVE-I (Pedersen et al., Drug Alcohol Depend 218:108363, 2020) with MOVE-G a combined group treatment for both alcohol use disorder and drug use disorder. The primary objective is to examine whether MOVE-G is non-inferior to MOVE-I in relation to abstinence from drug and/or alcohol, number of sessions received, and completion of treatment as planned. All participants will receive treatment based on cognitive behavioral therapy and motivational interviewing, vouchers for attendance and text reminders, as well as medication as needed (MOVE). Participants (n?=?300) will be recruited over a one-year period at four public treatment centers in four Danish municipalities. A short screening will determine eligibility and randomization status. Hereafter, participants will be randomized to the two treatment arms. A thorough baseline assessment will be conducted approximately 1 week after randomization. Follow-up assessments will be conducted at 9 months post-randomization. In addition, patients' use of drugs and alcohol, and patients' wellbeing will be measured in all sessions. The main outcome measures are drug and alcohol intake at 9 months follow-up, number of sessions attended, and dropout from treatment.DiscussionThe present study will examine the potential and efficacy of combined groups (patients with alcohol and drug disorders in the same group) versus individually based treatment both based on the treatment method MOVE (Pedersen et al., Drug Alcohol Depend 218:108363, 2020).Trial registrationISRCTN88025085 , registration date 30/06/2020.

Dataset Information

Epistatic evidence for gender-dependant slow neurotransmission signalling in substance use disorders: PPP1R12B versus PPP1R1B.

Publications

Epistatic evidence for gender-dependant slow neurotransmission signalling in substance use disorders: PPP1R12B versus PPP1R1B.

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