{"doi":"10.1016/j.bpsgos.2025.100448","title":"A Transcriptomic Signature of Depressive Symptoms in Late Life","abstract":"Depressive symptoms in late-life can impair daily function and accompany cognitive decline. However, the molecular mechanisms underlying these changes in the brain remain poorly understood. Differential expression analysis was performed on bulk tissue RNA sequencing data generated from dorsolateral prefrontal cortex samples of elderly participants in the Religious Orders Study and Memory and Aging Project (ROS/MAP: n=998, age at death mean=89.6). Bulk tissue RNA sequencing was analyzed against depressive symptoms measured prior to death, controlling for Alzheimer’s disease (AD) neuropathology, medication status, and lifestyle factors. Sex-stratified models were also tested. Increased abundance of the Prader-Willi syndrome-associated gene, PWAR1 (corrected p =5.47x10 -3 ) and CTDSPL2 (corrected p =0.03) were associated with a higher burden of depressive symptoms in the combined sample. An additional 14 genes showed suggestive associations, including several with known links to neuropsychiatric illness (e.g. ACVR2B-AS1, COL19A1) . Functional enrichment analysis revealed downregulation of aerobic metabolism and upregulation of both amino acid catabolism and DNA modification processes. Differential expression signatures were poorly correlated between males and females (Pearson r=0.12; 95%CI = [0.10,0.13]), and only the male group showed independently significant differential expression. Little overlap was found with previously published analyses of major depressive disorder. Building upon recently-published single-nucleus profiling, we present the largest-ever study of transcriptomic correlates of depressive symptoms in late-life, revealing new insights into sex-specific regulators. PWAR1 and CTDSPL2 were identified as putative markers of late-life depression in dorsolateral prefrontal cortex and warrant further study.","journal":"Biological Psychiatry Global Open Science","year":2025,"id":540030,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9329,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1427480,"name":"Melissa Misztal","orcid":"0000-0002-1191-4364","position":1,"is_corresponding":false},{"id":558701,"name":"Mu Yang","orcid":"0000-0001-7084-029X","position":2,"is_corresponding":false},{"id":356451,"name":"Thomas Delong","orcid":"0000-0002-3199-9385","position":3,"is_corresponding":false},{"id":560534,"name":"Shreejoy J. Tripathy","orcid":"0000-0002-1007-9061","position":4,"is_corresponding":false},{"id":375981,"name":"Jeffrey T. Dunn","orcid":"0000-0002-0287-1606","position":5,"is_corresponding":false},{"id":778,"name":"David A. Bennett","orcid":"0000-0003-3689-554X","position":6,"is_corresponding":false},{"id":771,"name":"Philip L. De Jager","orcid":"0000-0002-8057-2505","position":7,"is_corresponding":false},{"id":861528,"name":"Yanling Wang","orcid":"0000-0001-6645-9883","position":8,"is_corresponding":false},{"id":648093,"name":"Daniel Fisher","orcid":"0000-0003-3271-8327","position":9,"is_corresponding":false},{"id":332583,"name":"Hongxin Dong","orcid":"0000-0002-2469-070X","position":10,"is_corresponding":false},{"id":355527,"name":"Daniel Felsky","orcid":"0000-0003-1831-9848","position":11,"is_corresponding":false},{"id":998824,"name":"Stuart Matan-Lithwick","orcid":null,"position":0,"is_corresponding":true}],"reference_count":55,"raw_metadata":null,"created_at":"2026-07-19T02:52:34.520788Z","pmid":"40094036","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":[]}