{"doi":"10.1101/2023.02.27.23286048","title":"Novel <i>CYP1B1-RMDN2</i> Alzheimer’s disease locus identified by genome-wide association analysis of cerebral tau deposition on PET","abstract":"Abstract Determining the genetic architecture of Alzheimer’s disease (AD) pathologies can enhance mechanistic understanding and inform precision medicine strategies. Here, we performed a genome-wide association study of cortical tau quantified by positron emission tomography in 3,136 participants from 12 independent studies. The CYP1B1-RMDN2 locus was associated with tau deposition. The most significant signal was at rs2113389, which explained 4.3% of the variation in cortical tau, while APOE4 rs429358 accounted for 3.6%. rs2113389 was associated with higher tau and faster cognitive decline. Additive effects, but no interactions, were observed between rs2113389 and diagnosis, APOE4 , and Aβ positivity. CYP1B1 expression was upregulated in AD. rs2113389 was associated with higher CYP1B1 expression and methylation levels. Mouse model studies provided additional functional evidence for a relationship between CYP1B1 and tau deposition but not Aβ. These results may provide insight into the genetic basis of cerebral tau and novel pathways for therapeutic development in AD.","journal":"medRxiv","year":2023,"id":392235,"datarank":0.34338395727588417,"base_score":1.791759469228055,"endowment":1.791759469228055,"self_citation_contribution":0.26876392038420827,"citation_network_contribution":0.07462003689167591,"self_endowment_contribution":0.26876392038420827,"citer_contribution":0.07462003689167591,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":4,"citers_with_citation_signal":4,"citers_with_endowment":4,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9417,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":53156,"name":"Shannon L. Risacher","orcid":"0000-0002-3304-7943","position":1,"is_corresponding":false},{"id":278826,"name":"Liana G. Apostolova","orcid":"0000-0003-1823-2451","position":2,"is_corresponding":false},{"id":789797,"name":"Paula J. Bice","orcid":"0000-0001-5357-9966","position":3,"is_corresponding":false},{"id":479734,"name":"Jared R. Brosch","orcid":"0000-0002-6578-0584","position":4,"is_corresponding":false},{"id":749771,"name":"Rachael Deardorff","orcid":"0000-0002-1898-7187","position":5,"is_corresponding":false},{"id":253913,"name":"Kelley Faber","orcid":"0000-0003-3224-2736","position":6,"is_corresponding":false},{"id":324301,"name":"Martin R. Farlow","orcid":"0000-0001-7897-5471","position":7,"is_corresponding":false},{"id":40730,"name":"Tatiana Foroud","orcid":"0000-0002-5549-2212","position":8,"is_corresponding":false},{"id":324302,"name":"Sujuan Gao","orcid":"0000-0002-6741-6380","position":9,"is_corresponding":false},{"id":1149143,"name":"Thea Rosewood","orcid":"0000-0001-7025-0222","position":10,"is_corresponding":false},{"id":789796,"name":"Jun Pyo Kim","orcid":"0000-0003-4376-3107","position":11,"is_corresponding":false},{"id":278824,"name":"Kelly Nudelman","orcid":"0000-0003-4040-1717","position":12,"is_corresponding":false},{"id":301390,"name":"Meichen Yu","orcid":"0000-0003-4551-0269","position":13,"is_corresponding":false},{"id":229340,"name":"Paul Aisen","orcid":null,"position":14,"is_corresponding":false},{"id":55000,"name":"Reisa A. Sperling","orcid":"0000-0003-1535-6133","position":15,"is_corresponding":false},{"id":650892,"name":"Basavaraj Hooli","orcid":null,"position":16,"is_corresponding":false},{"id":396058,"name":"Sergey Shcherbinin","orcid":null,"position":17,"is_corresponding":false},{"id":579499,"name":"Diana Otero Svaldi","orcid":"0000-0001-6265-1931","position":18,"is_corresponding":false},{"id":49956,"name":"Clifford R. Jack","orcid":"0000-0001-7916-622X","position":19,"is_corresponding":false},{"id":51717,"name":"William J. Jagust","orcid":"0000-0002-4458-113X","position":20,"is_corresponding":false},{"id":66310,"name":"Susan Landau","orcid":null,"position":21,"is_corresponding":false},{"id":278823,"name":"Aparna Vasanthakumar","orcid":"0000-0003-3857-8812","position":22,"is_corresponding":false},{"id":251635,"name":"Jeffrey F. Waring","orcid":"0000-0002-7769-0367","position":23,"is_corresponding":false},{"id":236166,"name":"Vincent Doré","orcid":"0000-0002-8051-0558","position":24,"is_corresponding":false},{"id":236144,"name":"Simon M. Laws","orcid":"0000-0002-4355-7082","position":25,"is_corresponding":false},{"id":230035,"name":"Colin L. Masters","orcid":"0000-0003-3072-7940","position":26,"is_corresponding":false},{"id":236143,"name":"Tenielle Porter","orcid":"0000-0002-7887-6622","position":27,"is_corresponding":false},{"id":55007,"name":"Christopher C. Rowe","orcid":"0000-0003-3910-2453","position":28,"is_corresponding":false},{"id":236168,"name":"Victor L. Villemagne","orcid":"0000-0002-5832-9875","position":29,"is_corresponding":false},{"id":261835,"name":"Logan Dumitrescu","orcid":"0000-0002-9782-9944","position":30,"is_corresponding":false},{"id":254761,"name":"Timothy J. Hohman","orcid":"0000-0002-3377-7014","position":31,"is_corresponding":false},{"id":1063281,"name":"Julia B. Libby","orcid":null,"position":32,"is_corresponding":false},{"id":29931,"name":"Elizabeth C. Mormino","orcid":"0000-0002-4542-6537","position":33,"is_corresponding":false},{"id":261846,"name":"Rachel F. Buckley","orcid":"0000-0002-5356-5537","position":34,"is_corresponding":false},{"id":33059,"name":"Keith Johnson","orcid":"0000-0002-8578-5921","position":35,"is_corresponding":false},{"id":32029,"name":"Hyun‐Sik Yang","orcid":"0000-0002-8318-0443","position":36,"is_corresponding":false},{"id":27599,"name":"Ronald C. Petersen","orcid":"0000-0002-8178-6601","position":37,"is_corresponding":false},{"id":397191,"name":"Vijay K. Ramanan","orcid":"0000-0001-6591-8734","position":38,"is_corresponding":false},{"id":226058,"name":"Prashanthi Vemuri","orcid":"0000-0003-4286-0589","position":39,"is_corresponding":false},{"id":329924,"name":"Ann D. Cohen","orcid":"0000-0001-7395-9624","position":40,"is_corresponding":false},{"id":901055,"name":"Kang-Hsien Fan","orcid":"0000-0003-0121-3959","position":41,"is_corresponding":false},{"id":544014,"name":"M. Ilyas Kamboh","orcid":"0000-0002-3453-1438","position":42,"is_corresponding":false},{"id":245369,"name":"Oscar L. López","orcid":"0000-0002-8546-8256","position":43,"is_corresponding":false},{"id":778,"name":"David A. Bennett","orcid":"0000-0003-3689-554X","position":44,"is_corresponding":false},{"id":767175,"name":"Muhammad Ali","orcid":"0000-0002-1399-6631","position":45,"is_corresponding":false},{"id":301875,"name":"Tammie L.S. Benzinger","orcid":"0000-0002-8114-0552","position":46,"is_corresponding":false},{"id":230680,"name":"Carlos Cruchaga","orcid":"0000-0002-0276-2899","position":47,"is_corresponding":false},{"id":868904,"name":"Diana A. Hobbs","orcid":"0000-0001-7822-6411","position":48,"is_corresponding":false},{"id":771,"name":"Philip L. De Jager","orcid":"0000-0002-8057-2505","position":49,"is_corresponding":false},{"id":301856,"name":"Masashi Fujita","orcid":"0000-0002-1457-6233","position":50,"is_corresponding":false},{"id":285570,"name":"Vaishnavi Jadhav","orcid":"0009-0002-1227-9996","position":51,"is_corresponding":false},{"id":285576,"name":"Bruce T. Lamb","orcid":"0000-0001-8507-2561","position":52,"is_corresponding":false},{"id":463156,"name":"Andy P. Tsai","orcid":"0000-0001-6400-544X","position":53,"is_corresponding":false},{"id":39861,"name":"Isabel Castanho","orcid":"0000-0003-1413-626X","position":54,"is_corresponding":false},{"id":27801,"name":"Jonathan Mill","orcid":"0000-0003-1115-3224","position":55,"is_corresponding":false},{"id":51702,"name":"Michael W. Weiner","orcid":"0000-0002-0144-1954","position":56,"is_corresponding":false},{"id":54260,"name":"Alzheimer’s Disease Neuroimaging Initiative (ADNI)","orcid":null,"position":57,"is_corresponding":false},{"id":1165839,"name":"the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Study (A4 Study)","orcid":null,"position":58,"is_corresponding":false},{"id":1165840,"name":"Australian Imaging, Biomarker & Lifestyle Study (AIBL)","orcid":null,"position":59,"is_corresponding":false},{"id":27595,"name":"Andrew J. Saykin","orcid":"0000-0002-1376-8532","position":60,"is_corresponding":false},{"id":53300,"name":"Kwangsik Nho","orcid":"0000-0002-7624-3872","position":0,"is_corresponding":true}],"reference_count":85,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:18:52.232318Z","pmid":"36993271","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":[]}