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[Preprint]. 2023 Mar 22:2023.02.27.23286048.
doi: 10.1101/2023.02.27.23286048.

Novel CYP1B1-RMDN2 Alzheimer's disease locus identified by genome-wide association analysis of cerebral tau deposition on PET

Kwangsik Nho, Shannon L Risacher, Liana Apostolova, Paula J Bice, Jared Brosch, Rachael Deardorff, Kelley Faber, Martin R Farlow, Tatiana Foroud, Sujuan Gao, Thea Rosewood, Jun Pyo Kim, Kelly Nudelman, Meichen Yu, Paul Aisen, Reisa Sperling, Basavaraj Hooli, Sergey Shcherbinin, Diana Svaldi, Clifford R Jack, William J Jagust, Susan Landau, Aparna Vasanthakumar, Jeffrey F Waring, Vincent Doré, Simon M Laws, Colin L Masters, Tenielle Porter, Christopher C Rowe, Victor L Villemagne, Logan Dumitrescu, Timothy J Hohman, Julia B Libby, Elizabeth Mormino, Rachel F Buckley, Keith Johnson, Hyun-Sik Yang, Ronald C Petersen, Vijay K Ramanan, Prashanthi Vemuri, Ann D Cohen, Kang-Hsien Fan, M Ilyas Kamboh, Oscar L Lopez, David A Bennett, Muhammad Ali, Tammie Benzinger, Carlos Cruchaga, Diana Hobbs, Philip L De Jager, Masashi Fujita, Vaishnavi Jadhav, Bruce T Lamb, Andy P Tsai, Isabel Castanho, Jonathan Mill, Michael W Weiner; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Alzheimer’s Disease Neuroimaging Initiative – Department of Defense; Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Study (A4 Study); Australian Imaging, Biomarker & Lifestyle Study (AIBL); Andrew J Saykin

Novel CYP1B1-RMDN2 Alzheimer's disease locus identified by genome-wide association analysis of cerebral tau deposition on PET

Kwangsik Nho et al. medRxiv. .

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.

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