{"doi":"10.1101/2024.02.22.24303124","title":"Disentangling the shared genetics of ADHD, cannabis use disorder and cannabis use and prediction of cannabis use disorder in ADHD","abstract":"Abstract Cannabis use disorder (CUD) and cannabis use (CU) are prevalent conditions cooccurring with ADHD, but not much is known about the underlying shared genetics. Here we perform cross-disorder GWAS meta-analyses of ADHD and CUD or CU to identify pleiotropic risk loci and evaluate differences in the genetics of ADHD-CUD and ADHD-CU, and subsequently we dissect the polygenic architecture of CUD comorbidity in ADHD in the iPSYCH cohort. There was a higher genetic overlap of ADHD and CUD than observed for ADHD and CU and we found a significant direct effect of ADHD genetic risk on CUD with only a minor part (12%) mediated by the genetics of CU. We identified 36 genome-wide significant loci for ADHD-CUD and 10 loci for ADHD-CU, with concordant direction of effect on the phenotypes. Three different approaches identified DRD2 , which encodes the dopamine 2 receptor, as a risk gene for ADHD-CUD and, overall, ADHD-CUD risk genes were associated with high expression across several brain tissues and brain developmental stages, which was not observed for ADHD-CU genes. ADHD-CUD and ADHD-CU demonstrated similar genetic correlations with substance use phenotypes, while they differed significantly with respect to substance use disorder (SUD) phenotypes. ADHD-CUD individuals had significantly increased polygenic score (PGS) for psychiatric disorders compared to ADHD without CUD and increased burden of rare deleterious variants. Stratifying individuals with ADHD by their CUD-PGS revealed an absolute risk of 22% for comorbid CUD among the 20% of cases with the highest CUD-PGS, which was strikingly higher than the absolute risk of 1.6% observed among the 20% of controls with the highest CUD-PGS. Sex-specific analyses identified substantial differences in the absolute risk of comorbid CUD between males and females with ADHD, with a ∼10% higher CUD risk among males than females in the high-risk CUD-PGS group (24% risk for males and 14% risk for females).","journal":"medRxiv","year":2024,"id":492610,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9493,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":52578,"name":"Jinjie Duan","orcid":"0000-0002-3402-302X","position":1,"is_corresponding":false},{"id":869427,"name":"Daniel Levey","orcid":null,"position":2,"is_corresponding":false},{"id":648143,"name":"G. Bragi Walters","orcid":"0000-0002-5415-6487","position":3,"is_corresponding":false},{"id":230001,"name":"Emma C. Johnson","orcid":"0000-0003-0394-777X","position":4,"is_corresponding":false},{"id":5299,"name":"Thorgeir E. Thorgeirsson","orcid":"0000-0002-5149-7040","position":5,"is_corresponding":false},{"id":272673,"name":"VA Million Veteran Program","orcid":null,"position":6,"is_corresponding":false},{"id":108547,"name":"Thomas Werge","orcid":"0000-0003-1829-0766","position":7,"is_corresponding":false},{"id":1042903,"name":"Preben Bo Mortensen","orcid":"0000-0002-4782-1450","position":8,"is_corresponding":false},{"id":5388,"name":"Hreinn Stefánsson","orcid":"0000-0002-9331-6666","position":9,"is_corresponding":false},{"id":256445,"name":"Kāri Stefánsson","orcid":"0000-0003-1676-864X","position":10,"is_corresponding":false},{"id":5235,"name":"David M. Hougaard","orcid":"0000-0001-5928-3517","position":11,"is_corresponding":false},{"id":230004,"name":"Arpana Agrawal","orcid":"0000-0002-0313-793X","position":12,"is_corresponding":false},{"id":230005,"name":"Joel Gelernter","orcid":"0000-0002-4067-1859","position":13,"is_corresponding":false},{"id":104396,"name":"Jakob Grove","orcid":"0000-0003-2284-5744","position":14,"is_corresponding":false},{"id":5363,"name":"Anders D. Børglum","orcid":"0000-0001-8627-7219","position":15,"is_corresponding":false},{"id":62343,"name":"Ditte Demontis","orcid":"0000-0001-9124-2766","position":16,"is_corresponding":false},{"id":983765,"name":"Trine Tollerup Nielsen","orcid":null,"position":0,"is_corresponding":true}],"reference_count":78,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:08:56.210382Z","pmid":null,"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":[]}