{"doi":"10.1177/13872877251326288","title":"Brain and blood transcriptome-wide association studies identify five novel genes associated with Alzheimer's disease","abstract":"Background Genome-wide association studies (GWAS) have identified numerous genetic variants associated with Alzheimer's disease (AD), but their functional implications remain unclear. Transcriptome-wide association studies (TWAS) offer enhanced statistical power by analyzing genetic associations at the gene level rather than at the variant level, enabling assessment of how genetically-regulated gene expression influences AD risk. However, previous AD-TWAS have been limited by small expression quantitative trait loci (eQTL) reference datasets or reliance on AD-by-proxy phenotypes. Objective To perform the most powerful AD-TWAS to date using summary statistics from the largest available brain and blood cis -eQTL meta-analyses applied to the largest clinically-adjudicated AD GWAS. Methods We implemented the OTTERS TWAS pipeline to predict gene expression using the largest available cis -eQTL data from cortical brain tissue (MetaBrain; N = 2683) and blood (eQTLGen; N = 31,684), and then applied these models to AD-GWAS data (Cases = 21,982; Controls = 44,944). Results We identified and validated five novel gene associations in cortical brain tissue ( PRKAG1 , C3orf62 , LYSMD4 , ZNF439 , SLC11A2 ) and six genes proximal to known AD-related GWAS loci (Blood: MYBPC3 ; Brain: MTCH2 , CYB561 , MADD , PSMA5 , ANXA11 ). Further, using causal eQTL fine-mapping, we generated sparse models that retained the strength of the AD-TWAS association for MTCH2 , MADD , ZNF439 , CYB561 , and MYBPC3 . Conclusions Our comprehensive AD-TWAS discovered new gene associations and provided insights into the functional relevance of previously associated variants, which enables us to further understand the genetic architecture underlying AD risk.","journal":"Journal of Alzheimer s Disease","year":2025,"id":531226,"datarank":0.24141568686511508,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.0,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9518,"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":54608,"name":"Adam C. Naj","orcid":"0000-0002-9621-2942","position":1,"is_corresponding":false},{"id":405034,"name":"Anthony J. Griswold","orcid":"0000-0003-1925-7810","position":2,"is_corresponding":false},{"id":684718,"name":"Jennifer E. Below","orcid":"0000-0002-1346-1872","position":3,"is_corresponding":false},{"id":261839,"name":"William S. Bush","orcid":"0000-0002-9729-6519","position":4,"is_corresponding":false},{"id":1408137,"name":"Makaela Mews","orcid":"0009-0006-6416-7581","position":0,"is_corresponding":true}],"reference_count":68,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:51:14.579161Z","pmid":"40111921","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":[]}