Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP43 inclusions

被引：431

作者：

Van Deerlin, Vivianna M. ^{[1
]}

Sleiman, Patrick M. A.

Martinez-Lage, Maria ^{[1
,3
]}

Chen-Plotkin, Alice ^{[1
,4
]}

Wang, Li-San ^{[1
]}

Graff-Radford, Neill R. ^{[5
]}

Dickson, Dennis W. ^{[6
]}

Rademakers, Rosa ^{[6
]}

Boeve, Bradley F. ^{[7
]}

Grossman, Murray ^{[4
]}

Arnold, Steven E. ^{[4
,8
,9
]}

Mann, David M. A. ^{[10
]}

Pickering-Brown, Stuart M. ^{[10
]}

Seelaar, Harro ^{[11
]}

Heutink, Peter ^{[12
]}

van Swieten, John C. ^{[11
]}

Murrell, Jill R. ^{[13
,14
]}

Ghetti, Bernardino ^{[13
,14
]}

Spina, Salvatore ^{[13
,14
,15
]}

Grafman, Jordan ^{[16
]}

Hodges, John

Spillantini, Maria Grazia ^{[17
]}

Gilman, Sid ^{[18
]}

Lieberman, Andrew P. ^{[19
]}

Kaye, Jeffrey A. ^{[20
]}

Woltjer, Randall L. ^{[21
]}

Bigio, Eileen H. ^{[22
,23
]}

Mesulam, Marsel ^{[23
]}

al-Sarraj, Safa ^{[24
]}

Troakes, Claire ^{[25
]}

Rosenberg, Roger N. ^{[26
]}

White, Charles L., III ^{[27
]}

Ferrer, Isidro ^{[28
]}

Llado, Albert ^{[29
]}

Neumann, Manuela ^{[30
]}

Kretzschmar, Hans A. ^{[31
]}

Hulette, Christine Marie ^{[32
]}

Welsh-Bohmer, Kathleen A. ^{[33
,34
]}

Miller, Bruce L. ^{[35
]}

Alzualde, Ainhoa ^{[36
]}

Lopez de Munain, Adolfo ^{[37
]}

McKee, Ann C. ^{[38
,39
,40
]}

Gearing, Marla ^{[41
,42
,43
]}

Levey, Allan I. ^{[42
,43
,44
]}

Lah, James J. ^{[44
]}

Hardy, John ^{[45
,46
]}

Rohrer, Jonathan D. ^{[47
]}

Lashley, Tammaryn ^{[46
,48
]}

Mackenzie, Ian R. A. ^{[49
,50
]}

Feldman, Howard H. ^{[50
,51
,52
]}

机构：

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

[2] Univ Penn, Childrens Hosp Philadelphia, Ctr Appl Genom, Div Human Genet,Sch Med, Philadelphia, PA 19104 USA

[3] Univ Autonoma Barcelona, Dept Neurol, Hosp Santa Creu & St Pau, E-08193 Barcelona, Spain

[4] Univ Penn, Sch Med, Dept Neurol, Philadelphia, PA 19104 USA

[5] Mayo Coll Med, Dept Neurol, Jacksonville, FL USA

[6] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA

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

[8] Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA

[9] Univ Penn, Sch Med, Penn Memory Ctr, Philadelphia, PA 19104 USA

[10] Univ Manchester, Sch Community Based Med, Manchester, Lancs, England

[11] Erasmus MC, Rotterdam, Netherlands

[12] Vrije Univ Amsterdam, Med Ctr, Sect Med Genom, Dept Clin Genet, Amsterdam, Netherlands

[13] Indiana Univ Sch Med, Dept Pathol & Lab Med, Indianapolis, IN USA

[14] Indiana Univ Sch Med, Indiana Alzheimer Dis Ctr, Indianapolis, IN USA

[15] Univ Siena, Dept Neurol Neurosurg & Behav Sci, I-53100 Siena, Italy

[16] Natl Inst Neurol Disorders & Stroke, Cognit Neurosci Sect, Bethesda, MD USA

[17] Univ Cambridge, Cambridge Ctr Brain Repair, Dept Clin Neurosci, Cambridge, England

[18] Univ Michigan, Dept Neurol, Ann Arbor, MI USA

[19] Univ Michigan, Dept Pathol, Ann Arbor, MI USA

[20] Oregon Hlth & Sci Univ, Dept Neurol & Biomed Engn, Portland, OR 97201 USA

[21] Oregon Hlth & Sci Univ, Dept Pathol, Portland, OR 97201 USA

[22] Northwestern Univ, Feinberg Sch Med, Dept Pathol, Chicago, IL 60611 USA

[23] Northwestern Univ, Feinberg Sch Med, Cognit Neurol & Alzheimer Dis Ctr, Chicago, IL 60611 USA

[24] Kings Coll Hosp London, Inst Psychiat, Dept Clin Neuropathol, London, England

[25] Kings Coll Hosp London, MRC, London Neurodegenerat Dis Brain Bank, Inst Psychiat, London, England

[26] Univ Texas SW Med Ctr Dallas, Rush Alzheimers Dis Ctr, Dallas, TX 75390 USA

[27] Univ Texas SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA

[28] Hosp Univ Bellvitge, Inst Neuropatol, Inst Invest Biomed Bellvitge IDIBELL, Barcelona, Spain

[29] Hosp Clin Barcelona, Alzheimers Dis & Cognit Disorders Unit, Serv Neurol, Inst Clin Neurociencies, Barcelona, Spain

[30] Univ Zurich Hosp, Inst Neuropathol, CH-8091 Zurich, Switzerland

[31] Univ Munich, Ctr Neuropathol & Prion Res, Munich, Germany

[32] Duke Univ, Dept Pathol, Hlth Sci Ctr, Durham, NC 27706 USA

[33] Duke Univ, Med Ctr, Dept Psychiat, Durham, NC 27710 USA

[34] Duke Univ, Med Ctr, Bryan Alzheimers Dis Res Ctr, Durham, NC 27710 USA

[35] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA

[36] Hosp Donostia, Neurogenet Unit, Inst Biodonostia, San Sebastian, Spain

[37] Hosp Donostia, Serv Neurol, San Sebastian, Spain

[38] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA

[39] Boston Univ, Sch Med, Dept Pathol, Boston, MA 02118 USA

[40] Ctr Geriatr Res Educ & Clin, Bedford Vet Adm Med Ctr, Bedford, MA USA

[41] Emory Univ, Sch Med, Dept Pathol & Lab Med, Atlanta, GA 30322 USA

[42] Emory Univ, Sch Med, Alzheimers Dis Res Ctr, Atlanta, GA 30322 USA

[43] Emory Univ, Sch Med, Ctr Neurodegenerat Dis, Atlanta, GA 30322 USA

[44] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA

[45] UCL, Inst Neurol, Reta Lila Labs, London, England

[46] UCL, Inst Neurol, Dept Mol Neurosci, London, England

[47] UCL, Inst Neurol, Dementia Res Ctr, London, England

[48] UCL, Inst Neurol, Queen Sq Brain Bank Neurol Disorders, London, England

[49] Vancouver Gen Hosp, Dept Pathol, Vancouver, BC V5Z 1M9, Canada

[50] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada

来源：

NATURE GENETICS | 2010年 / 42卷 / 03期

基金：

英国医学研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; GLOBAL GENE-EXPRESSION; GENOTYPE DATA; DEMENTIA; PROGRANULIN; MUTATIONS; CONSENSUS; DISEASE; ONSET; FAMILIES;

D O I：

10.1038/ng.536

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA-binding protein (TDP-43) inclusions (FTLD-TDP) 1. FTLD-TDP is frequently familial, resulting from mutations in GRN (which encodes progranulin). We assembled an international collaboration to identify susceptibility loci for FTLD-TDP through a genome-wide association study of 515 individuals with FTLD-TDP. We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium block on 7p21 that contains TMEM106B. Three SNPs retained genome-wide significance following Bonferroni correction (top SNP rs1990622, P = 1.08 x 10(-11); odds ratio, minor allele (C) 0.61, 95% CI 0.53-0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P = 2 x 10(-4)). TMEM106B variants may confer risk of FTLD-TDP by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in individuals with mutations in GRN. Our data implicate variants in TMEM106B as a strong risk factor for FTLD-TDP, suggesting an underlying pathogenic mechanism.

引用

页码：234 / U34

页数：8

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