{"doi":"10.1016/j.ebiom.2020.103066","title":"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 (P meta <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","journal":"EBioMedicine","year":2020,"id":113051,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9467,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":533590,"name":"Juan Zhao","orcid":"0000-0002-9709-751X","position":1,"is_corresponding":false},{"id":533591,"name":"Chunnuan Chen","orcid":"0000-0002-8906-3184","position":2,"is_corresponding":false},{"id":328114,"name":"Jie Xu","orcid":"0000-0001-9452-2878","position":3,"is_corresponding":false},{"id":366492,"name":"Richard L. Bell","orcid":"0000-0002-0525-0485","position":4,"is_corresponding":false},{"id":432328,"name":"F. Scott Hall","orcid":"0000-0002-0822-4063","position":5,"is_corresponding":false},{"id":291967,"name":"George F. Koob","orcid":"0009-0002-9857-4493","position":6,"is_corresponding":false},{"id":109148,"name":"Nora D. Volkow","orcid":"0000-0001-6668-0908","position":7,"is_corresponding":false},{"id":149361,"name":"Hong Qing","orcid":null,"position":8,"is_corresponding":false},{"id":533592,"name":"Zhicheng Lin","orcid":"0000-0003-1372-422X","position":9,"is_corresponding":false},{"id":533589,"name":"Kefu Liu","orcid":"0000-0003-1168-8712","position":0,"is_corresponding":true}],"reference_count":79,"raw_metadata":null,"created_at":"2026-07-18T23:13:17.845093Z","pmid":"33096475","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}