{"doi":"10.1073/pnas.2527955123","title":"Identifying genome-by-childhood trauma interactions for depression using a forest-based approach in the UK Biobank and Adolescent Brain Cognitive Development Study","abstract":"Depression is shaped by both genetic and environmental factors, but genome-wide interaction studies (GWIS) often lack power to detect complex gene-environment (G × E) interactions. We applied a forest-based machine learning approach to 38,018 UK Biobank (UKB) participants, examining interactions between 285,677 single-nucleotide polymorphisms (SNPs) and three trauma types (childhood, adult, and catastrophic trauma). While GWIS detected no significant interactions, we identified 8,225 potentially important SNP-environment pairs across 1,732 genes, with childhood trauma contributing most prominently. Stratified heritability was higher among childhood trauma-exposed individuals (13.3%) versus those unexposed (6.0%). Many identified genes overlapped with known psychiatric risk loci and accounted for most of the SNP-based heritability. Thirteen top genes were replicated in the Adolescent Brain Cognitive Development Study. Our findings highlight the polygenic G × E nature of depression and the critical role of childhood trauma in modulating genetic risk, demonstrating the value of forest-based methods in detecting complex gene-environment interactions.","journal":"Proceedings of the National Academy of Sciences","year":2026,"id":985,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.1026,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2026-02-06","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":12875,"name":"Jeffrey R. Gruen","orcid":"0000-0001-7640-2071","position":1,"is_corresponding":false},{"id":12876,"name":"Heping Zhang","orcid":"0000-0002-0688-4076","position":2,"is_corresponding":false},{"id":12877,"name":"Fēi Dèng","orcid":"0000-0002-5385-083X","position":3,"is_corresponding":false},{"id":12874,"name":"Yue Hu","orcid":"0009-0002-2126-7559","position":0,"is_corresponding":true}],"reference_count":94,"raw_metadata":null,"created_at":"2026-03-01T18:20:47.508186Z","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":[]}