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

EBioMedicine. 2020 Nov:61:103066. doi: 10.1016/j.ebiom.2020.103066. Epub 2020 Oct 21.


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 terms

  • Animals
  • Brain / metabolism
  • Brain / pathology
  • Disease Models, Animal
  • Disease Susceptibility
  • Dopamine and cAMP-Regulated Phosphoprotein 32 / genetics*
  • Dopamine and cAMP-Regulated Phosphoprotein 32 / metabolism
  • Epistasis, Genetic*
  • Female
  • Gene Expression Regulation
  • Gene Regulatory Networks
  • Genetic Heterogeneity
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Male
  • Mice
  • Organ Specificity / genetics
  • Protein Phosphatase 1 / genetics*
  • Protein Phosphatase 1 / metabolism
  • Rats
  • Sex Factors
  • Substance-Related Disorders / diagnosis
  • Substance-Related Disorders / etiology*
  • Substance-Related Disorders / metabolism
  • Synaptic Transmission / genetics*


  • Dopamine and cAMP-Regulated Phosphoprotein 32
  • PPP1R1B protein, human
  • PPP1R12B protein, human
  • Protein Phosphatase 1