通过对PET脑tau蛋白沉积进行全基因组关联分析确定的新型阿尔茨海默病基因座。

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

作者信息

Nho Kwangsik, Risacher Shannon L, Apostolova Liana, Bice Paula J, Brosch Jared, Deardorff Rachael, Faber Kelley, Farlow Martin R, Foroud Tatiana, Gao Sujuan, Rosewood Thea, Kim Jun Pyo, Nudelman Kelly, Yu Meichen, Aisen Paul, Sperling Reisa, Hooli Basavaraj, Shcherbinin Sergey, Svaldi Diana, Jack Clifford R, Jagust William J, Landau Susan, Vasanthakumar Aparna, Waring Jeffrey F, Doré Vincent, Laws Simon M, Masters Colin L, Porter Tenielle, Rowe Christopher C, Villemagne Victor L, Dumitrescu Logan, Hohman Timothy J, Libby Julia B, Mormino Elizabeth, Buckley Rachel F, Johnson Keith, Yang Hyun-Sik, Petersen Ronald C, Ramanan Vijay K, Vemuri Prashanthi, Cohen Ann D, Fan Kang-Hsien, Kamboh M Ilyas, Lopez Oscar L, Bennett David A, Ali Muhammad, Benzinger Tammie, Cruchaga Carlos, Hobbs Diana, De Jager Philip L, Fujita Masashi, Jadhav Vaishnavi, Lamb Bruce T, Tsai Andy P, Castanho Isabel, Mill Jonathan, Weiner Michael W, Saykin Andrew J

出版信息

medRxiv. 2023 Mar 22:2023.02.27.23286048. doi: 10.1101/2023.02.27.23286048.

DOI:10.1101/2023.02.27.23286048

PMID:36993271

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10055458/

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 locus was associated with tau deposition. The most significant signal was at rs2113389, which explained 4.3% of the variation in cortical tau, while 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, , and Aβ positivity. expression was upregulated in AD. rs2113389 was associated with higher expression and methylation levels. Mouse model studies provided additional functional evidence for a relationship between 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.

摘要

确定阿尔茨海默病（AD）病理的遗传结构可以增强对其机制的理解，并为精准医学策略提供依据。在此，我们对来自12项独立研究的3136名参与者进行了一项全基因组关联研究，通过正电子发射断层扫描对皮质tau进行量化。该基因座与tau沉积相关。最显著的信号位于rs2113389，它解释了皮质tau变异的4.3%，而rs429358占3.6%。rs2113389与更高的tau水平和更快的认知衰退相关。在rs2113389与诊断、以及Aβ阳性之间观察到加性效应，但没有相互作用。在AD中表达上调。rs2113389与更高的表达和甲基化水平相关。小鼠模型研究为与tau沉积之间的关系提供了额外的功能证据，但与Aβ无关。这些结果可能为脑tau的遗传基础提供见解，并为AD治疗开发提供新的途径。