Human Molecular Genetics Advance Access published online on February 4, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp059
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A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis
1 Department of Neuroscience, University of Turin, Turin, Italy 2 Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD, USA 3 Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK 4 Molecular Genetics Unit, Department of Clinical Pathology, A.S.O. O.I.R.M.-S.Anna, Turin, Italy 5 Molecular Genetics Unit, Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD, USA 6 Department of Molecular Neuroscience and Reta Lila Weston Institute of Neurological Studies, Institute of Neurology, Queen Square, London, UK 7 Department of Neurology, Chang Gung Memorial Hospital and College of Medicine, aiwan 8 Salvatore Maugeri Foundation, Lissone, Italy 9 Computational Biology Core, Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD, USA 10 Center for Human Genetics, Duke University Medical Center, Durham, North Carolina, USA 11 Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA 12 Epidemiology Research and Information Center, Durham VAMC, North Carolina, USA 13 Longitudinal Studies Section, Clinical Research Branch, National Institute on Aging, Baltimore, Maryland, USA 14 Geriatric Unit, Azienda Sanitaria di Firenze, Florence, Italy 15 Laboratory of Epidemiology, Demography and Biometry, National Institute on Aging, Bethesda, Maryland, USA 16 Department of Science and Biomedical Technology, University of Milan, Italy 17 INSPE, San Raffaele Scientific Institute, Milan 18 Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD 19 Department of Epidemiology, Harvard School of Public Health, Boston, MA 20 Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg/Munich, Germany 21 Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany 22 Department of Neuroscience, Neurology Section, University of Siena, Siena, Italy 23 Department of Neuroscience, Ophthalmology and Genetics, University of Genoa, Italy 24 Department of Clinical Neurosciences, University of Palermo, Italy 25 Department of Neurological Sciences, Second University of Naples, Italy 26 Neurological Institute, Catholic University and I.CO.M.M. Association for ALS Reseach, Rome, Italy 27 Department of Neuroscience, S. Agostino- Estense Hospital, and University of Modena, Italy 28 Center for Diagnosis and Cure of Rare Diseases, Department of Neurology, Bellaria Hospital, Bologna, Italy 29 Department of Neuroscience, University of Pisa, Italy 30 University Department of Clinical Neurosciences, Institute of Neurology, University College London, London 31 Department of Neurology, Penn State College of Medicine, Hershey, PA, USA 32 Department of Neurosurgery, Penn State College of Medicine, Hershey, PA, USA 33 Department of Neurology, Cleveland Clinic, Cleveland, OH 34 Neurogenomics Division, Translational Genomics Institute (TGEN), Phoenix, AZ 35 Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK 36 Institute of Clinical Neurobiology, University of Wuerzburg, Wuerzburg, Germany 37 The ALS Association, Palm Harbor, FL, USA 38 Department of Neurology, Johns Hopkins University, Baltimore, MD, USA
* Corresponding author: Bryan J. Traynor, National Institutes of Health, Building 35, Room 1A/1000, 35 Convent Drive, Bethesda, MD 20892-3720, Email: traynorb{at}mail.nih.gov; Phone: (301) 451 7606; Fax: (301) 451-7295
Received December 2, 2008; Revised February 2, 2009; Accepted February 2, 2009
The cause of sporadic 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: we followed our initial genome-wide association study of 545,066 SNPs in 553 individuals with ALS and 2,338 controls by testing the 7,600 most associated SNPs from the first stage in three independent cohorts consisting of 2,160 cases and 3,008 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=1.17 and 1.18, and P-value=6.98x10–7 and 1.16x10–6), were located on chromosome 7p13.3 within a 175kb 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 (odds ratio=1.18 and 1.19, P-value=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 has been made available online to facilitate such future endevours.
+ These authors contributed equally to this work.
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