CYP1B1-RMDN2 Alzheimer's disease endophenotype locus identified for cerebral tau PET

被引：1

作者：

Nho, Kwangsik ^{[1
,2
,3
,4
]}

Risacher, Shannon L. ^{[1
,3
]}

Apostolova, Liana G. ^{[1
,3
,5
,6
]}

Bice, Paula J. ^{[1
,3
]}

Brosch, Jared R. ^{[3
,5
]}

Deardorff, Rachael ^{[3
,5
]}

Faber, Kelley ^{[6
,7
]}

Farlow, Martin R. ^{[3
,5
]}

Foroud, Tatiana ^{[3
,6
,7
]}

Gao, Sujuan ^{[3
,8
]}

Rosewood, Thea ^{[1
,2
,3
]}

Kim, Jun Pyo ^{[1
,2
,3
]}

Nudelman, Kelly ^{[3
,6
,7
]}

Yu, Meichen ^{[1
,3
]}

Aisen, Paul ^{[9
]}

Sperling, Reisa ^{[10
]}

Hooli, Basavaraj ^{[11
]}

Shcherbinin, Sergey ^{[11
]}

Svaldi, Diana ^{[11
]}

Jack Jr, Clifford R. ^{[12
]}

Jagust, William J. ^{[13
]}

Landau, Susan ^{[13
]}

Vasanthakumar, Aparna ^{[14
]}

Waring, Jeffrey F. ^{[14
]}

Dore, Vincent ^{[15
,16
]}

Laws, Simon M. ^{[17
]}

Masters, Colin L. ^{[18
,19
]}

Porter, Tenielle ^{[17
]}

Rowe, Christopher C. ^{[16
,18
,19
]}

Villemagne, Victor L. ^{[16
,20
]}

Dumitrescu, Logan ^{[21
,22
]}

Hohman, Timothy J. ^{[21
,22
]}

Libby, Julia B. ^{[21
]}

Mormino, Elizabeth ^{[23
]}

Buckley, Rachel F. ^{[10
]}

Johnson, Keith ^{[10
,24
]}

Yang, Hyun-Sik ^{[10
,25
]}

Petersen, Ronald C. ^{[26
]}

Ramanan, Vijay K. ^{[26
]}

Ertekin-Taner, Niluefer ^{[27
,28
]}

Vemuri, Prashanthi ^{[12
]}

Cohen, Ann D. ^{[20
]}

Fan, Kang-Hsien ^{[29
]}

Kamboh, M. Ilyas ^{[29
]}

Lopez, Oscar L. ^{[20
,30
]}

Bennett, David A. ^{[31
]}

Ali, Muhammad ^{[32
]}

Benzinger, Tammie ^{[33
]}

Cruchaga, Carlos ^{[32
,34
]}

Hobbs, Diana ^{[33
]}

机构：

[1] Indiana Univ Sch Med, Ctr Neuroimaging, Dept Radiol & Imaging Sci, Indianapolis, IN 46204 USA

[2] Indiana Univ Sch Med, Ctr Computat Biol & Bioinformat, Indianapolis, IN 46204 USA

[3] Indiana Univ Sch Med, Indiana Alzheimers Dis Res Ctr, Indianapolis, IN 46204 USA

[4] Indiana Univ, Dept BioHlth Informat, Indianapolis, IN 46204 USA

[5] Indiana Univ Sch Med, Dept Neurol, Indianapolis, IN 46204 USA

[6] Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46204 USA

[7] Indiana Univ Sch Med, Natl Centralized Repository Alzheimers Dis & Rela, Indianapolis, IN USA

[8] Indiana Univ Sch Med, Dept Biostat, Indianapolis, IN USA

[9] Univ Southern Calif, Keck Sch Med, Dept Neurol, San Diego, CA USA

[10] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Boston, MA USA

[11] Eli Lilly & Co, Indianapolis, IN USA

[12] Mayo Clin, Dept Radiol, Rochester, FL USA

[13] Univ Calif Berkeley, UC Berkeley Helen Wills Neurosci Inst, Berkeley, CA USA

[14] AbbVie, Genom Res Ctr, N Chicago, IL USA

[15] CSIRO Hlth & Biosecur, Melbourne, Australia

[16] Austin Hlth, Dept Mol Imaging & Therapy, Heidelberg, Australia

[17] Edith Cowan Univ, Ctr Precis Hlth, Sch Med & Hlth Sci, Joondalup, Australia

[18] Florey Inst Neurosci & Mental Hlth, Parkville, Australia

[19] Univ Melbourne, Parkville, Australia

[20] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA

[21] Vanderbilt Univ, Med Ctr, Vanderbilt Memory & Alzheimers Ctr, Nashville, TN USA

[22] Vanderbilt Univ, Med Ctr, Vanderbilt Genet Inst, Nashville, TN USA

[23] Stanford Univ, Dept Neurol & Neurol Sci, Stanford, CA USA

[24] Harvard Med Sch, Dept Radiol, Massachusetts Gen Hosp, Boston, MA USA

[25] Harvard Med Sch, Brigham & Womens Hosp, Ctr Alzheimer Res & Treatment, Dept Neurol, Boston, MA USA

[26] Mayo Clin, Dept Neurol, Rochester, MN USA

[27] Mayo Clin, Dept Neurol, Jacksonville, FL USA

[28] Mayo Clin, Dept Neurosci, Jacksonville, FL USA

[29] Univ Pittsburgh, Dept Human Genet, Pittsburgh, PA USA

[30] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA USA

[31] Rush Univ, Rush Med Coll, Dept Neurol Sci, Chicago, IL USA

[32] Washington Univ, Dept Psychiat, St Louis, MO USA

[33] Washington Univ, Sch Med, Dept Radiol, St Louis, MO USA

[34] Washington Univ, Sch Med, NeuroGenom & Informat Ctr, St Louis, MO USA

[35] Columbia Univ, Ctr Translat & Computat Neuroimmunol, Irving Med Ctr, Dept Neurol, New York, NY USA

[36] Columbia Univ, Taub Inst Res Alzheimers Dis & Aging Brain, Irving Med Ctr, New York, NY USA

[37] Indiana Univ Sch Med, Stark Neurosci Res Inst, Indianapolis, IN USA

[38] Stanford Univ, Sch Med, Wu Tsai Neurosci Inst, Stanford, CA USA

[39] Univ Exeter, Med Sch, Dept Clin & Biomed Sci, Exeter, England

[40] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA USA

[41] Univ Calif San Francisco, Dept Radiol, San Francisco, CA USA

[42] Univ Calif San Francisco, Dept Med, San Francisco, CA USA

[43] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA

[44] Dept Vet Affairs Med Ctr, San Francisco, CA USA

来源：

NATURE COMMUNICATIONS | 2024年 / 15卷 / 01期

基金：

美国国家卫生研究院; 英国医学研究理事会; 英国惠康基金; 澳大利亚国家健康与医学研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; MOUSE MODEL; OXIDATIVE STRESS; MICROGLIAL ACTIVATION; TRANSGENIC MICE; RISK LOCI; MEMORY; EXPRESSION; ACCUMULATION; METAANALYSIS;

D O I：

10.1038/s41467-024-52298-2

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：14

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