CYP1B1-RMDN2 Alzheimer’s disease endophenotype locus identified for cerebral tau PET
Kwangsik Nho, Shannon L. Risacher, Liana G. Apostolova, Paula J. Bice, Jared R. Brosch, Rachael Deardorff, Kelley Faber, Martin R. Farlow, Tatiana Foroud, Sujuan Gao, Thea Rosewood, Jun Pyo Kim, Kelly Nudelman, Meichen Yu, Paul Aisen, Reisa A. Sperling, Basavaraj Hooli, Sergey Shcherbinin, Diana Otero 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 C. Mormino, Rachel F. Buckley, Keith A. Johnson, Hyun‐Sik Yang, Ronald C. Petersen, Vijay K. Ramanan, Nilüfer Ertekin‐Taner, Prashanthi Vemuri, Ann D. Cohen, Kang-Hsien Fan, M. Ilyas Kamboh, Oscar L. López, David A. Bennett, Muhammad Ali, Tammie L.S. Benzinger, Carlos Cruchaga, Diana A. Hobbs, Philip L. De Jager, Masashi Fujita, Vaishnavi Jadhav, Bruce T. Lamb, Andy P. Tsai, Isabel Castanho, Jonathan Mill, Michael W. Weiner, for the Alzheimer’s Disease Neuroimaging Initiative (ADNI), the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Study (A4 Study) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN), the Australian Imaging, Biomarker & Lifestyle Study (AIBL), Andrew J. Saykin
Abstract
Determining the genetic architecture of Alzheimer's disease pathologies can enhance mechanistic understanding and inform precision medicine strategies. Here, we perform a genome-wide association study of cortical tau quantified by positron emission tomography in 3046 participants from 12 independent studies. The CYP1B1-RMDN2 locus is associated with tau deposition. The most significant signal is at rs2113389, explaining 4.3% of the variation in cortical tau, while APOE4 rs429358 accounts for 3.6%. rs2113389 is associated with higher tau and faster cognitive decline. Additive effects, but no interactions, are observed between rs2113389 and diagnosis, APOE4, and amyloid beta positivity. CYP1B1 expression is upregulated in AD. rs2113389 is associated with higher CYP1B1 expression and methylation levels. Mouse model studies provide additional functional evidence for a relationship between CYP1B1 and tau deposition but not amyloid beta. These results provide insight into the genetic basis of cerebral tau deposition and support novel pathways for therapeutic development in AD.