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

Nho, K.; Risacher, S. L.; Apostolova, L.; Bice, P. J.; Brosch, J.; Deardorff, R.; Faber, K.; Farlow, M. R.; Foroud, T.; Gao, S.; Rosewood, T.; Kim, J. P.; Nudelman, K.; Yu, M.; Aisen, P.; Sperling, R.; Hooli, B.; Shcherbinin, S.; Svaldi, D.; Jack, C. R.; Jagust, W. J.; Landau, S.; Vasanthakumar, A.; Waring, J. F.; Dore, V.; Laws, S. M.; Masters, C. L.; Porter, T.; Rowe, C. C.; Villemagne, V. L.; Dumitrescu, L.; Hohman, T. J.; Libby, J. B.; Mormino, E.; Buckley, R. F.; Johnson, K.; Yang, H.-S.; Petersen, R. C.; Ramanan, V. K.; Vemuri, P.; Cohen, A. D.; Fan, K.-H.; Kamboh, M. I.; Lopez, O. L.; B

2023-03-22 radiology and imaging
10.1101/2023.02.27.23286048 medRxiv
Show abstract

Determining the genetic architecture of Alzheimers 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 A{beta} 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 A{beta}. These results may provide insight into the genetic basis of cerebral tau and novel pathways for therapeutic development in AD.

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