Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis

被引：301

作者：

van Es, Michael A.

Veldink, Jan H.

Saris, Christiaan G. J.

Blauw, Hylke M.

van Vught, Paul W. J.

Birve, Anna ^{[2
]}

Lemmens, Robin ^{[3
,4
]}

Schelhaas, Helenius J. ^{[5
]}

Groen, Ewout J. N.

Huisman, Mark H. B.

van der Kooi, Anneke J. ^{[6
]}

de Visser, Marianne ^{[6
]}

Dahlberg, Caroline ^{[2
]}

Estrada, Karol ^{[7
]}

Rivadeneira, Fernando ^{[7
,8
]}

Hofman, Albert ^{[8
]}

Zwarts, Machiel J. ^{[5
]}

van Doormaal, Perry T. C.

Rujescu, Dan ^{[9
]}

Strengman, Eric ^{[10
,11
]}

Giegling, Ina ^{[9
]}

Muglia, Pierandrea ^{[12
]}

Tomik, Barbara ^{[13
]}

Slowik, Agnieszka ^{[13
]}

Uitterlinden, Andre G. ^{[7
,8
]}

Hendrich, Corinna ^{[14
]}

Waibel, Stefan ^{[14
]}

Meyer, Thomas ^{[15
]}

Ludolph, Albert C. ^{[14
]}

Glass, Jonathan D. ^{[16
]}

Purcell, Shaun ^{[17
]}

Cichon, Sven ^{[18
,19
]}

Noethen, Markus M. ^{[18
,19
]}

Wichmann, H-Erich ^{[20
,21
,22
]}

Schreiber, Stefan ^{[23
,24
]}

Vermeulen, Sita H. H. M. ^{[25
]}

Kiemeney, Lambertus A. ^{[26
,27
]}

Wokke, John H. J. ^{[1
]}

Cronin, Simon ^{[28
,29
]}

McLaughlin, Russell L. ^{[29
,30
]}

Hardiman, Orla ^{[29
,30
]}

Fumoto, Katsumi ^{[31
]}

Pasterkamp, R. Jeroen ^{[31
]}

Meininger, Vincent ^{[32
]}

Melki, Judith ^{[33
]}

Leigh, P. Nigel ^{[34
]}

Shaw, Christopher E. ^{[34
]}

Landers, John E. ^{[35
,36
]}

Al-Chalabi, Ammar ^{[34
]}

Brown, Robert H., Jr. ^{[35
,36
]}

机构：

[1] Univ Med Ctr Utrecht, Dept Neurol, Rudolf Magnus Inst Neurosci, Utrecht, Netherlands

[2] Umea Univ Hosp, Inst Clin Neurosci, S-90185 Umea, Sweden

[3] Katholieke Univ Leuven VIB, Vesalius Res Ctr, Leuven, Belgium

[4] Univ Leuven, Dept Neurol, Univ Hosp Leuven, Louvain, Belgium

[5] Radboud Univ Nijmegen, Dept Neurology Clin Neurophysiol, Donders Inst Brain Cognit & Behav, Ctr Neurosci,Med Ctr, NL-6525 ED Nijmegen, Netherlands

[6] Univ Amsterdam, Acad Med Ctr, Dept Neurol, NL-1105 AZ Amsterdam, Netherlands

[7] Erasmus MC, Dept Internal Med, Genet Lab, Rotterdam, Netherlands

[8] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands

[9] Univ Munich, Dept Psychiat, Div Mol & Clin Neurobiol, D-8000 Munich, Germany

[10] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands

[11] Univ Med Ctr Utrecht, Rudolf Magnus Inst, Utrecht, Netherlands

[12] GlaxoSmithKline R&D, Med Genet, Verona, Italy

[13] Jagiellonian Univ, Dept Neurol, Krakow, Poland

[14] Univ Ulm, Dept Neurol, D-7900 Ulm, Germany

[15] Humboldt Univ, Dept Neurol, Charite Univ Hosp, Berlin, Germany

[16] Emory Univ, Dept Neurol, Atlanta, GA 30322 USA

[17] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

[18] Univ Bonn, Inst Human Genet, D-5300 Bonn, Germany

[19] Univ Bonn, Dept Genom, Life & Brain Ctr, D-5300 Bonn, Germany

[20] German Res Ctr Environm Hlth, Inst Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany

[21] Univ Munich, Inst Med Informat Biometry & Epidemiol, Chair Epidemiol, Munich, Germany

[22] Univ Munich, Klinikum Grosshadern, D-8000 Munich, Germany

[23] Univ Kiel, Inst Clin Mol Biol, Kiel, Germany

[24] Univ Kiel, Dept Gen Internal Med, Kiel, Germany

[25] Radboud Univ Nijmegen, Dept Epidemiol Biostat & HTA, Dept Human Genet, Med Ctr, NL-6525 ED Nijmegen, Netherlands

[26] Radboud Univ Nijmegen, Dept Urol, Med Ctr, NL-6525 ED Nijmegen, Netherlands

[27] Comprehens Canc Ctr E, Nijmegen, Netherlands

[28] Royal Coll Surgeons Ireland, Dept Clin Neurol Sci, Dublin 2, Ireland

[29] Beaumont Hosp, Dept Neurol, Dublin 9, Ireland

[30] Trinity Coll Dublin, Inst Neurosci, Dublin, Ireland

[31] Univ Med Ctr Utrecht, Dept Neurosci & Pharmacol, Rudolf Magnus Inst Neurosci, Utrecht, Netherlands

[32] Hop La Pitie Salpetriere, Dept Neurol, AP HP, Paris, France

[33] Hadassah Univ Hosp, Dept Human Genet, IL-91120 Jerusalem, Israel

[34] Kings Coll London, Dept Clin Neurosci, MRC, Ctr Neurodegenerat Res,Inst Psychiat, London WC2R 2LS, England

[35] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA USA

[36] Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA USA

[37] Univ Calif Los Angeles, Ctr Neurobehav Genet, Los Angeles, CA USA

来源：

NATURE GENETICS | 2009年 / 41卷 / 10期

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

FRONTOTEMPORAL DEMENTIA; CONFERS SUSCEPTIBILITY; CHROMOSOME; 9P; POPULATION; DISEASE; VARIANTS; RELEASE; LINKAGE; HAPMAP; DESIGN;

D O I：

10.1038/ng.442

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

We conducted a genome-wide association study among 2,323 individuals with sporadic amyotrophic lateral sclerosis (ALS) and 9,013 control subjects and evaluated all SNPs with P < 1.0 x 10(-4) in a second, independent cohort of 2,532 affected individuals and 5,940 controls. Analysis of the genome-wide data revealed genome-wide significance for one SNP, rs12608932, with P = 1.30 x 10(-9). This SNP showed robust replication in the second cohort (P = 1.86 x 10(-6)), and a combined analysis over the two stages yielded P = 2.53 x 10(-14). The rs12608932 SNP is located at 19p13.3 and maps to a haplotype block within the boundaries of UNC13A, which regulates the release of neurotransmitters such as glutamate at neuromuscular synapses. Follow-up of additional SNPs showed genome-wide significance for two further SNPs (rs2814707, with P = 7.45 x 10(-9), and rs3849942, with P = 1.01 x 10(-8)) in the combined analysis of both stages. These SNPs are located at chromosome 9p21.2, in a linkage region for familial ALS with frontotemporal dementia found previously in several large pedigrees.

引用

页码：1083 / U53

页数：6

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