Novel CYP1B1-RMDN2 Alzheimer’s disease locus identified by genome-wide association analysis of cerebral tau deposition on PET
Novel CYP1B1-RMDN2 Alzheimer’s disease locus identified by genome-wide association analysis of cerebral tau deposition on PET
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.
Lamb Bruce T.、Hobbs Diana、De Jager Philip L.、Castanho Isabel、Mill Jonathan、Alzheimer?ˉs Disease Neuroimaging Initiative (ADNI)、Landau Susan、Dor¨| Vincent、Laws Simon M.、Porter Tenielle、Villemagne Victor L、Dumitrescu Logan、Mormino Elizabeth、Johnson Keith、Petersen Ronald C.、Vemuri Prashanthi、Fan Kang-Hsien、Benzinger Tammie、Cruchaga Carlos、Risacher Shannon L.、Apostolova Liana、Bice Paula J.、Brosch Jared、Deardorff Rachael、Foroud Tatiana、Rosewood Thea、Nudelman Kelly、Hooli Basavaraj、Svaldi Diana、Aisen Paul、Rowe Christopher C.、the Alzheimer?ˉs Disease Neuroimaging Initiative ¨C Department of Defense、Farlow Martin R.、Fujita Masashi、Lopez Oscar L.、Saykin Andrew J.、Tsai Andy P.、Waring Jeffrey F.、Vasanthakumar Aparna、Kim Jun Pyo、Australian Imaging, Biomarker & Lifestyle Study (AIBL)、Gao Sujuan、Faber Kelley、Jack Clifford R.、Libby Julia B.、Yu Meichen、Weiner Michael W.、Sperling Reisa、the Anti-Amyloid Treatment in Asymptomatic Alzheimer?ˉs Study (A4 Study)、Ali Muhammad、Shcherbinin Sergey、Ramanan Vijay K.、Buckley Rachel F.、Hohman Timothy J.、Cohen Ann D.、Jagust William J.、Masters Colin L.、Bennett David A.、Kamboh M. Ilyas、Nho Kwangsik、Yang Hyun-Sik、Jadhav Vaishnavi
神经病学、精神病学基础医学遗传学
Alzheimer’s diseaseImaging geneticstau PETRMDN2CYP1B1
Lamb Bruce T.,Hobbs Diana,De Jager Philip L.,Castanho Isabel,Mill Jonathan,Alzheimer?ˉs Disease Neuroimaging Initiative (ADNI),Landau Susan,Dor¨| Vincent,Laws Simon M.,Porter Tenielle,Villemagne Victor L,Dumitrescu Logan,Mormino Elizabeth,Johnson Keith,Petersen Ronald C.,Vemuri Prashanthi,Fan Kang-Hsien,Benzinger Tammie,Cruchaga Carlos,Risacher Shannon L.,Apostolova Liana,Bice Paula J.,Brosch Jared,Deardorff Rachael,Foroud Tatiana,Rosewood Thea,Nudelman Kelly,Hooli Basavaraj,Svaldi Diana,Aisen Paul,Rowe Christopher C.,the Alzheimer?ˉs Disease Neuroimaging Initiative ¨C Department of Defense,Farlow Martin R.,Fujita Masashi,Lopez Oscar L.,Saykin Andrew J.,Tsai Andy P.,Waring Jeffrey F.,Vasanthakumar Aparna,Kim Jun Pyo,Australian Imaging, Biomarker & Lifestyle Study (AIBL),Gao Sujuan,Faber Kelley,Jack Clifford R.,Libby Julia B.,Yu Meichen,Weiner Michael W.,Sperling Reisa,the Anti-Amyloid Treatment in Asymptomatic Alzheimer?ˉs Study (A4 Study),Ali Muhammad,Shcherbinin Sergey,Ramanan Vijay K.,Buckley Rachel F.,Hohman Timothy J.,Cohen Ann D.,Jagust William J.,Masters Colin L.,Bennett David A.,Kamboh M. Ilyas,Nho Kwangsik,Yang Hyun-Sik,Jadhav Vaishnavi.Novel CYP1B1-RMDN2 Alzheimer’s disease locus identified by genome-wide association analysis of cerebral tau deposition on PET[EB/OL].(2025-03-28)[2025-06-07].https://www.medrxiv.org/content/10.1101/2023.02.27.23286048.点此复制
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