Epistatic evidence for gender-dependant slow neurotransmission signalling in substance use disorders: PPP1R12B versus PPP1R1B
Kefu Liu,
Juan Zhao,
Chunnuan Chen,
Jie Xu,
Richard L. Bell,
Frank S. Hall,
George F. Koob,
Nora D. Volkow,
Hong Qing,
Zhicheng Lin
Affiliations
Kefu Liu
School of Life Science, Beijing Institute of Technology, 100081 Beijing, China; Laboratory of Psychiatric Neurogenomics, McLean Hospital, Belmont, MA 02478, United States of America
Juan Zhao
School of Life Science, Beijing Institute of Technology, 100081 Beijing, China; Laboratory of Psychiatric Neurogenomics, McLean Hospital, Belmont, MA 02478, United States of America
Chunnuan Chen
Laboratory of Psychiatric Neurogenomics, McLean Hospital, Belmont, MA 02478, United States of America; Department of Neurology, the Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, P. R. China
Jie Xu
Department of Computer Information Systems, Bentley University, Waltham, MA, 02452, United States of America
Richard L. Bell
Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States of America
Frank S. Hall
Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, Ohio 43614, United States of America
George F. Koob
National Institute on Drug Abuse and National Institute of Alcohol Abuse and Alcoholism, Bethesda, Maryland, 20892 United States of America
Nora D. Volkow
National Institute on Drug Abuse and National Institute of Alcohol Abuse and Alcoholism, Bethesda, Maryland, 20892 United States of America
Hong Qing
School of Life Science, Beijing Institute of Technology, 100081 Beijing, China; Correspondence: Hong Qing, School of Life Science, Beijing Institute of Technology, No 5 South Zhongguancun Street, Haidian District, 100081 Beijing, China
Zhicheng Lin
Laboratory of Psychiatric Neurogenomics, McLean Hospital, Belmont, MA 02478, United States of America; Correspondence: Zhicheng Lin, McLean Hospital Mailstop 318, 115 Mill Street, Belmont, MA 02478, United States of America
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).
