GWAS of Cerebrospinal Fluid Tau Levels Identifies Risk Variants for Alzheimer's Disease

被引：298

作者：

Cruchaga, Carlos ^{[1
,7
]}

Kauwe, John S. K. ^{[8
]}

Harari, Oscar ^{[1
]}

Jin, Sheng Chih ^{[1
]}

Cai, Yefei ^{[1
]}

Karch, Celeste M. ^{[1
]}

Benitez, Bruno A. ^{[1
]}

Jeng, Amanda T. ^{[1
]}

Skorupa, Tara ^{[1
]}

Carrell, David ^{[1
]}

Bertelsen, Sarah ^{[1
]}

Bailey, Matthew ^{[8
]}

McKean, David ^{[8
]}

Shulman, Joshua M. ^{[9
,10
,11
]}

De Jager, Philip L. ^{[12
,13
,14
]}

Chibnik, Lori ^{[12
,13
,14
]}

Bennett, David A. ^{[15
,16
]}

Arnold, Steve E. ^{[17
]}

Harold, Denise ^{[18
]}

Sims, Rebecca ^{[18
]}

Gerrish, Amy ^{[18
]}

Williams, Julie ^{[18
]}

Van Deerlin, Vivianna M. ^{[19
]}

Lee, Virginia M. -Y. ^{[19
]}

Shaw, Leslie M. ^{[19
]}

Trojanowski, John Q. ^{[19
]}

Haines, Jonathan L. ^{[20
]}

Mayeux, Richard ^{[21
,22
]}

Pericak-Vance, Margaret A. ^{[23
,24
]}

Farrer, Lindsay A. ^{[25
]}

Schellenberg, Gerard D. ^{[26
]}

Peskind, Elaine R. ^{[27
,28
,29
]}

Galasko, Douglas ^{[30
]}

Fagan, Anne M. ^{[2
,6
,7
]}

Holtzman, David M. ^{[2
,5
,6
,7
]}

Morris, John C. ^{[2
,3
,6
]}

Goate, Alison M. ^{[2
,4
,6
,7
]}

机构：

[1] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA

[2] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA

[3] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA

[4] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA

[5] Washington Univ, Sch Med, Dept Dev Biol, St Louis, MO 63110 USA

[6] Washington Univ, Sch Med, Knight Alzheimers Dis Res Ctr, St Louis, MO 63110 USA

[7] Washington Univ, Sch Med, Hope Ctr Neurol Disorders, St Louis, MO 63110 USA

[8] Brigham Young Univ, Dept Biol, Provo, UT 84602 USA

[9] Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA

[10] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

[11] Texas Childrens Hosp, Jan & Dan Duncan Neurol Res Inst, Houston, TX 77030 USA

[12] Brigham & Womens Hosp, Program Translat NeuroPsychiat Genom, Inst Neurosci, Dept Neurol, Boston, MA 02115 USA

[13] Harvard Univ, Sch Med, Boston, MA 02115 USA

[14] Broad Inst Harvard Univ & MIT, Program Med & Populat Genet, Cambridge, MA 02142 USA

[15] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60062 USA

[16] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60062 USA

[17] Univ Penn, Dept Psychiat & Neurol, Philadelphia, PA 19104 USA

[18] Cardiff Univ, Inst Psychol Med & Clin Neurosci, Cardiff CF10 3AT, Wales

[19] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

[20] Vanderbilt Univ, Vanderbilt Ctr Human Genet Res, Dept Mol Physiol & Biophys, Nashville, TN 37235 USA

[21] Columbia Univ, Taub Inst Alzheimers Dis & Aging Brain, Dept Neurol, New York, NY 10027 USA

[22] Columbia Univ, Gertrude H Sergievsky Ctr, New York, NY 10027 USA

[23] Univ Miami, John P Hussman Inst Human Genom, Miami, FL 33124 USA

[24] Univ Miami, Dr John T Macdonald Fdn Dept Human Genet, Miami, FL 33124 USA

[25] Boston Univ, Dept Biostat, Med Genet Program, Boston, MA 02118 USA

[26] Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA 19104 USA

[27] Univ Washington, Sch Med, Dept Psychiat, Seattle, WA 99204 USA

[28] Univ Washington, Sch Med, Dept Behav Sci, Seattle, WA 99204 USA

[29] Mental Illness Res Educ & Clin Ctr, Vet Affairs Northwest Network, Seattle, WA 99204 USA

[30] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA

来源：

NEURON | 2013年 / 78卷 / 02期

基金：

英国惠康基金; 美国国家卫生研究院; 英国医学研究理事会;

关键词：

SINGLE-NUCLEOTIDE POLYMORPHISMS; CSF; PROTEIN; ASSOCIATION; PHOSPHORYLATION; NEUROPATHOLOGY; EXPRESSION; BIOMARKERS; A-BETA(42); DIAGNOSIS;

D O I：

10.1016/j.neuron.2013.02.026

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Cerebrospinal fluid (CSF) tau, tau phosphorylated at threonine 181 (ptau), and A beta(42) are established biomarkers for Alzheimer's disease (AD) and have been used as quantitative traits for genetic analyses. We performed the largest genome-wide association study for cerebrospinal fluid (CSF) tau/ptau levels published to date (n = 1,269), identifying three genome-wide significant loci for CSF tau and ptau: rs9877502 (p = 4.89 x 10(-9) for tau) located at 3q28 between GEMC1 and OSTN, rs514716 (p = 1.07 x10(-8) and p = 3.22 x 10(-9) for tau and ptau, respectively), located at 9p24.2 within GLIS3 and rs6922617 (p = 3.58 x 10(-8) for CSF ptau) at 6p21.1 within the TREM gene cluster, a region recently reported to harbor rare variants that increase AD risk. In independent data sets, rs9877502 showed a strong association with risk for AD, tangle pathology, and global cognitive decline (p = 2.67 x 10(-4), 0.039, 4.86 x 10(-5), respectively) illustrating how this endophenotype-based approach can be used to identify new AD risk loci.

引用

页码：256 / 268

页数：13

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