TY - JOUR
T1 - CYP1B1-RMDN2 Alzheimer’s disease endophenotype locus identified for cerebral tau PET
AU - for the Alzheimer’s Disease Neuroimaging Initiative (ADNI)
AU - the Department of Defense Alzheimer’s Disease Neuroimaging Initiative (DoD-ADNI)
AU - the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Study (A4 Study) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN)
AU - the Australian Imaging, Biomarker & Lifestyle Study (AIBL)
AU - Nho, Kwangsik
AU - Risacher, Shannon L.
AU - Apostolova, Liana G.
AU - Bice, Paula J.
AU - Brosch, Jared R.
AU - Deardorff, Rachael
AU - Faber, Kelley
AU - Farlow, Martin R.
AU - Foroud, Tatiana
AU - Gao, Sujuan
AU - Rosewood, Thea
AU - Kim, Jun Pyo
AU - Nudelman, Kelly
AU - Yu, Meichen
AU - Aisen, Paul
AU - Sperling, Reisa
AU - Hooli, Basavaraj
AU - Shcherbinin, Sergey
AU - Svaldi, Diana
AU - Jack, Clifford R.
AU - Jagust, William J.
AU - Landau, Susan
AU - Vasanthakumar, Aparna
AU - Waring, Jeffrey F.
AU - Doré, Vincent
AU - Laws, Simon M.
AU - Masters, Colin L.
AU - Porter, Tenielle
AU - Rowe, Christopher C.
AU - Villemagne, Victor L.
AU - Dumitrescu, Logan
AU - Hohman, Timothy J.
AU - Libby, Julia B.
AU - Mormino, Elizabeth
AU - Buckley, Rachel F.
AU - Johnson, Keith
AU - Yang, Hyun Sik
AU - Petersen, Ronald C.
AU - Ramanan, Vijay K.
AU - Ertekin-Taner, Nilüfer
AU - Vemuri, Prashanthi
AU - Cohen, Ann D.
AU - Fan, Kang Hsien
AU - Kamboh, M. Ilyas
AU - Lopez, Oscar L.
AU - Bennett, David A.
AU - Ali, Muhammad
AU - Benzinger, Tammie
AU - Cruchaga, Carlos
AU - Hobbs, Diana
AU - De Jager, Philip L.
AU - Fujita, Masashi
AU - Jadhav, Vaishnavi
AU - Lamb, Bruce T.
AU - Tsai, Andy P.
AU - Castanho, Isabel
AU - Mill, Jonathan
AU - Weiner, Michael W.
AU - Saykin, Andrew J.
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/12
Y1 - 2024/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85204511869&partnerID=8YFLogxK
U2 - 10.1038/s41467-024-52298-2
DO - 10.1038/s41467-024-52298-2
M3 - Article
C2 - 39304655
AN - SCOPUS:85204511869
SN - 2041-1723
VL - 15
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 8251
ER -