NovelCYP1B1-RMDN2Alzheimer’s disease locus identified by genome-wide association analysis of cerebral tau deposition on PET

Abstract

AbstractDetermining 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. TheCYP1B1-RMDN2locus was associated with tau deposition. The most significant signal was at rs2113389, which explained 4.3% of the variation in cortical tau, whileAPOE4rs429358 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.CYP1B1expression was upregulated in AD. rs2113389 was associated with higherCYP1B1expression and methylation levels. Mouse model studies provided additional functional evidence for a relationship betweenCYP1B1and 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.