{"doi":"10.1101/2025.09.25.25336663","title":"Mapping genetic effects on splicing in ten thousand post-mortem brain samples reveals novel mediators of neurological disease risk","abstract":"Abstract Alternative splicing shapes isoform diversity and gene dosage but how genetic variation impacts splicing in brain disease is still not fully characterized. We assembled BigBrain, a multi-ancestry resource of 10,725 bulk RNA-seq profiles with matched genotypes from 4,656 individuals across 43 tissue-cohort pairs, and mapped 68,358 cis -sQTLs affecting 10,966 genes using mixed-model meta-analysis. Using SuSiE, we finemapped over half of these sQTLs into 95% credible sets, frequently to a single variant near splice sites. We further annotated variants predicted to alter dosage through frameshifts or nonsense-mediated decay or disrupt protein domains. Colocalization with seven neurodegenerative and psychiatric GWAS highlighted 97 loci where alternative splicing appears to mediate genetic risk. Among sQTL-eQTL pairs with colocalization probability ≥ 0.8 (posterior probability of a shared causal variant), half shared credible-set variants, showing that splicing can complement or act independently of expression. Mechanistic examples include CAMLG (Parkinson’s), ZDHHC2 (Schizophrenia), and CLU (Alzheimer’s).","journal":"medRxiv","year":2025,"id":556783,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":29.844511487584125,"corpus_rank":8690,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":true,"is_dataset_confidence":0.7296,"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":1456879,"name":"Kailash BP","orcid":null,"position":1,"is_corresponding":false},{"id":1452535,"name":"Winston H. Cuddleston","orcid":"0000-0001-7897-3185","position":2,"is_corresponding":false},{"id":1165246,"name":"Benjamin Müller","orcid":"0009-0004-9712-6378","position":3,"is_corresponding":false},{"id":1452534,"name":"Beomjin Jang","orcid":"0009-0008-9056-1480","position":4,"is_corresponding":false},{"id":808017,"name":"Alex Tokolyi","orcid":"0000-0003-4222-7484","position":5,"is_corresponding":false},{"id":63165,"name":"Hong‐Hee Won","orcid":"0000-0001-5719-0552","position":6,"is_corresponding":false},{"id":238156,"name":"Jack Humphrey","orcid":"0000-0002-6274-6620","position":7,"is_corresponding":false},{"id":15885,"name":"Towfique Raj","orcid":"0000-0002-9355-5704","position":8,"is_corresponding":false},{"id":12616,"name":"David A. Knowles","orcid":"0000-0002-7408-146X","position":9,"is_corresponding":false},{"id":1383877,"name":"Aline Réal","orcid":"0000-0002-9437-4411","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:55:13.130091Z","pmid":"41040686","pmcid":"PMC12486005","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":[]}