{"doi":"10.1101/2024.07.13.24310361","title":"Genome-wide meta-analyses of non-response to antidepressants identify novel loci and potential drugs","abstract":"Antidepressants exhibit a considerable variation in efficacy, and increasing evidence suggests that individual genetics contribute to antidepressant treatment response. Here, we combined data on antidepressant non-response measured using rating scales for depressive symptoms, questionnaires of treatment effect, and data from electronic health records, to increase statistical power to detect genomic loci associated with non-response to antidepressants in a total sample of 135,471 individuals prescribed antidepressants. We performed genome-wide association meta-analyses, leave-one-out polygenic prediction, and bioinformatics analyses for genetically informed drug prioritization. We identified two novel loci associated with non-response to antidepressants and showed significant polygenic prediction in independent samples. In addition, we investigated drugs that target proteins likely involved in mechanisms underlying antidepressant non-response, and shortlisted drugs that warrant further replication and validation of their potential to reduce depressive symptoms in individuals who do not respond to first-line antidepressant medications. These results suggest that meta-analyses of GWAS utilizing real-world measures of treatment outcomes can increase sample sizes to improve the discovery of variants associated with non-response to antidepressants.","journal":"medRxiv","year":2024,"id":484910,"datarank":0.31191623125197543,"base_score":2.0794415416798357,"endowment":2.0794415416798357,"self_citation_contribution":0.31191623125197543,"citation_network_contribution":0.0,"self_endowment_contribution":0.31191623125197543,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9394,"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":347761,"name":"Tuuli Jürgenson","orcid":"0000-0002-9998-1640","position":1,"is_corresponding":false},{"id":1020195,"name":"Guðmundur Einarsson","orcid":"0000-0002-1326-2339","position":2,"is_corresponding":false},{"id":228008,"name":"Brittany L. Mitchell","orcid":"0000-0002-9050-1516","position":3,"is_corresponding":false},{"id":1041858,"name":"Arvid Harder","orcid":"0000-0002-5984-9207","position":4,"is_corresponding":false},{"id":745053,"name":"Luis M. García‐Marín","orcid":"0000-0003-4731-6558","position":5,"is_corresponding":false},{"id":272375,"name":"Kristi Krebs","orcid":"0000-0003-0494-2751","position":6,"is_corresponding":false},{"id":1327501,"name":"Yuhao Lin","orcid":"0000-0002-8244-8495","position":7,"is_corresponding":false},{"id":860722,"name":"Ying Xiong","orcid":"0009-0009-8835-202X","position":8,"is_corresponding":false},{"id":1327502,"name":"Yi Lü","orcid":"0000-0001-7832-3019","position":9,"is_corresponding":false},{"id":228610,"name":"Sara Hägg","orcid":"0000-0002-2452-1500","position":10,"is_corresponding":false},{"id":240745,"name":"Miguel E. Rentería","orcid":"0000-0003-4626-7248","position":11,"is_corresponding":false},{"id":5254,"name":"Sarah E. Medland","orcid":"0000-0003-1382-380X","position":12,"is_corresponding":false},{"id":5188,"name":"Naomi R. Wray","orcid":"0000-0001-7421-3357","position":13,"is_corresponding":false},{"id":5340,"name":"Nicholas G. Martin","orcid":"0000-0003-4069-8020","position":14,"is_corresponding":false},{"id":1327963,"name":"Christopher Hüebel","orcid":null,"position":15,"is_corresponding":false},{"id":215,"name":"Gerome Breen","orcid":"0000-0003-2053-1792","position":16,"is_corresponding":false},{"id":5299,"name":"Thorgeir E. Thorgeirsson","orcid":"0000-0002-5149-7040","position":17,"is_corresponding":false},{"id":5388,"name":"Hreinn Stefánsson","orcid":"0000-0002-9331-6666","position":18,"is_corresponding":false},{"id":256445,"name":"Kāri Stefánsson","orcid":"0000-0003-1676-864X","position":19,"is_corresponding":false},{"id":5036,"name":"Lili Milani","orcid":"0000-0002-5323-3102","position":20,"is_corresponding":false},{"id":52934,"name":"Ole A. Andreassen","orcid":"0000-0002-4461-3568","position":21,"is_corresponding":false},{"id":256438,"name":"Kevin S. O’Connell","orcid":"0000-0002-6865-8795","position":22,"is_corresponding":false},{"id":922486,"name":"Elise Koch","orcid":"0000-0003-3727-4470","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:07:47.633574Z","pmid":"39072048","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":[]}