A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis

被引：91

作者：

Chio, Adriano ^{[2
]}

Schymick, Jennifer C. ^{[3
]}

Restagno, Gabriella ^{[4
]}

Scholz, Sonja W. ^{[1
]}

Lombardo, Federica ^{[4
]}

Lai, Shiao-Lin ^{[1
,5
,6
,7
]}

Mora, Gabriele ^{[8
]}

Fung, Hon-Chung ^{[7
]}

Britton, Angela ^{[1
]}

Arepalli, Sampath ^{[1
]}

Gibbs, J. Raphael ^{[5
,6
,9
]}

Nalls, Michael ^{[1
]}

Berger, Stephen

Kwee, Lydia Coulter ^{[10
,11
]}

Oddone, Eugene Z. ^{[11
,12
]}

Ding, Jinhui ^{[9
]}

Crews, Cynthia

Rafferty, Ian

Washecka, Nicole

Hernandez, Dena ^{[1
,5
,6
]}

Ferrucci, Luigi ^{[13
]}

Bandinelli, Stefania ^{[14
]}

Guralnik, Jack ^{[15
]}

Macciardi, Fabio ^{[16
]}

Torri, Federica ^{[16
]}

Lupoli, Sara ^{[17
]}

Chanock, Stephen J. ^{[18
]}

Thomas, Gilles ^{[18
]}

Hunter, David J. ^{[18
,19
]}

Gieger, Christian ^{[20
,21
]}

Wichmann, H. Erich ^{[20
,21
]}

Calvo, Andrea ^{[2
]}

Mutani, Roberto ^{[2
]}

Battistini, Stefania ^{[22
]}

Giannini, Fabio ^{[22
]}

Caponnetto, Claudia ^{[23
]}

Mancardi, Giovanni Luigi ^{[23
]}

La Bella, Vincenzo ^{[24
]}

Valentino, Francesca ^{[24
]}

Monsurro, Maria Rosaria ^{[25
]}

Tedeschi, Gioacchino ^{[25
]}

Marinou, Kalliopi ^{[8
]}

Sabatelli, Mario ^{[26
,27
]}

Conte, Amelia ^{[26
,27
]}

Mandrioli, Jessica ^{[28
,29
]}

Sola, Patrizia ^{[28
,29
]}

Salvi, Fabrizio ^{[30
]}

Bartolomei, Ilaria ^{[30
]}

Siciliano, Gabriele ^{[31
]}

Carlesi, Cecilia ^{[31
]}

机构：

[1] NIA, Neurogenet Lab, NIH, Mol Genet Unit, Bethesda, MD 20892 USA

[2] Univ Turin, Dept Neurosci, Turin, Italy

[3] Univ Oxford, Dept Physiol Anat & Genet, Oxford, England

[4] ASO OIRM S Anna, Mol Genet Unit, Dept Clin Pathol, Turin, Italy

[5] Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England

[6] Inst Neurol, Reta Lila Weston Inst Neurol Studies, London WC1N 3BG, England

[7] Chang Gung Mem Hosp, Dept Neurol, Kaohsiung, Taiwan

[8] Salvatore Maugeri Fdn, Lissone, Italy

[9] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA

[10] Duke Univ, Med Ctr, Ctr Human Genet, Durham, NC USA

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

[12] Durham VAMC, Epidemiol Res & Informat Ctr, Durham, NC USA

[13] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA

[14] Azienda Sanit Firenze, Geriatr Unit, Florence, Italy

[15] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA

[16] Univ Milan, Dept Sci & Biomed Technol, Milan, Italy

[17] Ist Sci San Raffaele, INSPE, I-20132 Milan, Italy

[18] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA

[19] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA

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

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

[22] Univ Siena, Dept Neurosci, Neurol Sect, I-53100 Siena, Italy

[23] Univ Genoa, Dept Neurosci Ophthalmol & Genet, Genoa, Italy

[24] Univ Palermo, Dept Clin Neurosci, Sicily, Italy

[25] Univ Naples 2, Dept Neurol Sci, Caserta, Italy

[26] Catholic Univ, Neurol Inst, Rome, Italy

[27] ICOMM Assoc ALS Res, Rome, Italy

[28] S Agostino Estense Hosp, Dept Neurosci, Modena, Italy

[29] Univ Modena, I-41100 Modena, Italy

[30] Bellaria Hosp, Dept Neurol, Ctr Diag & Cure Rare Dis, Bologna, Italy

[31] Univ Pisa, Dept Neurosci, Pisa, Italy

[32] UCL, Univ Dept Clin Neurosci, Inst Neurol, London, England

[33] Penn State Coll Med, Dept Neurol, Hershey, PA USA

[34] Penn State Coll Med, Dept Neurosurg, Hershey, PA USA

[35] Cleveland Clin, Dept Neurol, Cleveland, OH 44106 USA

[36] Translat Genom Inst TGEN, Neurogenom Div, Phoenix, AZ USA

[37] UCL Inst Neurol, Dept Neurodegenerat Dis, London, England

[38] Univ Wurzburg, Inst Clin Neurobiol, Wurzburg, Germany

[39] ALS Assoc, Palm Harbor, FL USA

[40] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA

来源：

HUMAN MOLECULAR GENETICS | 2009年 / 18卷 / 08期

基金：

美国国家卫生研究院;

关键词：

GENETICS; DISEASE; ALS; SUSCEPTIBILITY; MUTATIONS;

D O I：

10.1093/hmg/ddp059

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The cause of sporadic amyotrophic lateral sclerosis (ALS) is largely unknown, but genetic factors are thought to play a significant role in determining susceptibility to motor neuron degeneration. To identify genetic variants altering risk of ALS, we undertook a two-stage genome-wide association study (GWAS): we followed our initial GWAS of 545 066 SNPs in 553 individuals with ALS and 2338 controls by testing the 7600 most associated SNPs from the first stage in three independent cohorts consisting of 2160 cases and 3008 controls. None of the SNPs selected for replication exceeded the Bonferroni threshold for significance. The two most significantly associated SNPs, rs2708909 and rs2708851 [odds ratio (OR) = 1.17 and 1.18, and P-values = 6.98 x 10(-7) and 1.16 x 10(-6)], were located on chromosome 7p13.3 within a 175 kb linkage disequilibrium block containing the SUNC1, HUS1 and C7orf57 genes. These associations did not achieve genome-wide significance in the original cohort and failed to replicate in an additional independent cohort of 989 US cases and 327 controls (OR = 1.18 and 1.19, P-values = 0.08 and 0.06, respectively). Thus, we chose to cautiously interpret our data as hypothesis-generating requiring additional confirmation, especially as all previously reported loci for ALS have failed to replicate successfully. Indeed, the three loci (FGGY, ITPR2 and DPP6) identified in previous GWAS of sporadic ALS were not significantly associated with disease in our study. Our findings suggest that ALS is more genetically and clinically heterogeneous than previously recognized. Genotype data from our study have been made available online to facilitate such future endeavors.

引用

页码：1524 / 1532

页数：9

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