SNCA variants are associated with increased risk for multiple system atrophy†‡
Corresponding Author
Sonja W. Scholz MD
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD
Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, London, United Kingdom
S.W.S., H.H., C.S., and M.S. contributed equally to this work.
Laboratory of Neurogenetics, National Institute on Aging, 35 Convent Drive, Room 1A-1014, 20892 Bethesda, MDSearch for more papers by this authorHenry Houlden MD, PhD, MRCP
Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, London, United Kingdom
S.W.S., H.H., C.S., and M.S. contributed equally to this work.
Search for more papers by this authorClaudia Schulte
Hertie-Institute for Clinical Brain Research, Department of Neurodegenerative Diseases, University of Tuebingen, Tuebingen, Germany
S.W.S., H.H., C.S., and M.S. contributed equally to this work.
Search for more papers by this authorManu Sharma PhD
Hertie-Institute for Clinical Brain Research, Department of Neurodegenerative Diseases, University of Tuebingen, Tuebingen, Germany
S.W.S., H.H., C.S., and M.S. contributed equally to this work.
Search for more papers by this authorAbi Li BSc
Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, London, United Kingdom
Search for more papers by this authorDaniela Berg MD
Hertie-Institute for Clinical Brain Research, Department of Neurodegenerative Diseases, University of Tuebingen, Tuebingen, Germany
Search for more papers by this authorAnna Melchers MD
Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, London, United Kingdom
Search for more papers by this authorReema Paudel MSc
Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, London, United Kingdom
Search for more papers by this authorJ. Raphael Gibbs BS
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD
Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, London, United Kingdom
Search for more papers by this authorJavier Simon-Sanchez PhD
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD
Search for more papers by this authorCoro Paisan-Ruiz PhD
Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, London, United Kingdom
Search for more papers by this authorJose Bras MS
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD
Search for more papers by this authorJinhui Ding PhD
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD
Search for more papers by this authorHonglei Chen MD, PhD
Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC
Search for more papers by this authorBryan J. Traynor MD, MMSc, MRCPI
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD
Search for more papers by this authorSampath Arepalli BS
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD
Search for more papers by this authorRyan R. Zonozi BA
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD
Search for more papers by this authorTamas Revesz MD, FRCPath
Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, London, United Kingdom
Search for more papers by this authorJanice Holton MD, PhD, FRCPath
Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, London, United Kingdom
Search for more papers by this authorNick Wood MD, PhD, FRCP
Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, London, United Kingdom
Search for more papers by this authorAndrew Lees MD, FRCP
Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, London, United Kingdom
Search for more papers by this authorWolfgang Oertel MD
Centre of Nervous Diseases, Philipps-University of Marburg, Marburg, Germany
Search for more papers by this authorUllrich Wüllner MD, PhD
Department of Neurology, University Hospital of Bonn Medical Center, Bonn, Germany
Search for more papers by this authorStefano Goldwurm MD, PhD
Parkinson Institute, Istituti Clinici di Perfezionamento, Milano, Italy
Search for more papers by this authorMaria Teresa Pellecchia MD, PhD
Department of Neurological Sciences, University Federico II, Napoli, Italy
Search for more papers by this authorThomas Illig PhD
Institute of Epidemiology, German Research Center for Environmental Health, Helmholtz Zentrum München, Munich, Germany
Search for more papers by this authorOlaf Riess MD, PhD
Department of Medical Genetics, Institute of Human Genetics, University of Tuebingen, Tuebingen, Germany
Search for more papers by this authorHubert H. Fernandez MD
Department of Neurology and Neurosurgery, University of Florida, Gainesville, FL
Search for more papers by this authorRamon L. Rodriguez MD
Department of Neurology and Neurosurgery, University of Florida, Gainesville, FL
Search for more papers by this authorMichael S. Okun MD
Department of Neurology and Neurosurgery, University of Florida, Gainesville, FL
Search for more papers by this authorWerner Poewe MD
Department of Neurology, Medical University Innsbruck, Innsbruck, Austria
Search for more papers by this authorGregor K. Wenning MD, PhD
Department of Neurology, Medical University Innsbruck, Innsbruck, Austria
Search for more papers by this authorJohn A. Hardy PhD, MD (Hon), FMedSci
Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, London, United Kingdom
Search for more papers by this authorAndrew B. Singleton PhD
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD
A.B.S. and T.G. are joint last authors.
Search for more papers by this authorThomas Gasser MD
Hertie-Institute for Clinical Brain Research, Department of Neurodegenerative Diseases, University of Tuebingen, Tuebingen, Germany
A.B.S. and T.G. are joint last authors.
Search for more papers by this authorCorresponding Author
Sonja W. Scholz MD
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD
Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, London, United Kingdom
S.W.S., H.H., C.S., and M.S. contributed equally to this work.
Laboratory of Neurogenetics, National Institute on Aging, 35 Convent Drive, Room 1A-1014, 20892 Bethesda, MDSearch for more papers by this authorHenry Houlden MD, PhD, MRCP
Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, London, United Kingdom
S.W.S., H.H., C.S., and M.S. contributed equally to this work.
Search for more papers by this authorClaudia Schulte
Hertie-Institute for Clinical Brain Research, Department of Neurodegenerative Diseases, University of Tuebingen, Tuebingen, Germany
S.W.S., H.H., C.S., and M.S. contributed equally to this work.
Search for more papers by this authorManu Sharma PhD
Hertie-Institute for Clinical Brain Research, Department of Neurodegenerative Diseases, University of Tuebingen, Tuebingen, Germany
S.W.S., H.H., C.S., and M.S. contributed equally to this work.
Search for more papers by this authorAbi Li BSc
Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, London, United Kingdom
Search for more papers by this authorDaniela Berg MD
Hertie-Institute for Clinical Brain Research, Department of Neurodegenerative Diseases, University of Tuebingen, Tuebingen, Germany
Search for more papers by this authorAnna Melchers MD
Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, London, United Kingdom
Search for more papers by this authorReema Paudel MSc
Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, London, United Kingdom
Search for more papers by this authorJ. Raphael Gibbs BS
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD
Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, London, United Kingdom
Search for more papers by this authorJavier Simon-Sanchez PhD
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD
Search for more papers by this authorCoro Paisan-Ruiz PhD
Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, London, United Kingdom
Search for more papers by this authorJose Bras MS
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD
Search for more papers by this authorJinhui Ding PhD
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD
Search for more papers by this authorHonglei Chen MD, PhD
Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC
Search for more papers by this authorBryan J. Traynor MD, MMSc, MRCPI
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD
Search for more papers by this authorSampath Arepalli BS
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD
Search for more papers by this authorRyan R. Zonozi BA
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD
Search for more papers by this authorTamas Revesz MD, FRCPath
Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, London, United Kingdom
Search for more papers by this authorJanice Holton MD, PhD, FRCPath
Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, London, United Kingdom
Search for more papers by this authorNick Wood MD, PhD, FRCP
Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, London, United Kingdom
Search for more papers by this authorAndrew Lees MD, FRCP
Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, London, United Kingdom
Search for more papers by this authorWolfgang Oertel MD
Centre of Nervous Diseases, Philipps-University of Marburg, Marburg, Germany
Search for more papers by this authorUllrich Wüllner MD, PhD
Department of Neurology, University Hospital of Bonn Medical Center, Bonn, Germany
Search for more papers by this authorStefano Goldwurm MD, PhD
Parkinson Institute, Istituti Clinici di Perfezionamento, Milano, Italy
Search for more papers by this authorMaria Teresa Pellecchia MD, PhD
Department of Neurological Sciences, University Federico II, Napoli, Italy
Search for more papers by this authorThomas Illig PhD
Institute of Epidemiology, German Research Center for Environmental Health, Helmholtz Zentrum München, Munich, Germany
Search for more papers by this authorOlaf Riess MD, PhD
Department of Medical Genetics, Institute of Human Genetics, University of Tuebingen, Tuebingen, Germany
Search for more papers by this authorHubert H. Fernandez MD
Department of Neurology and Neurosurgery, University of Florida, Gainesville, FL
Search for more papers by this authorRamon L. Rodriguez MD
Department of Neurology and Neurosurgery, University of Florida, Gainesville, FL
Search for more papers by this authorMichael S. Okun MD
Department of Neurology and Neurosurgery, University of Florida, Gainesville, FL
Search for more papers by this authorWerner Poewe MD
Department of Neurology, Medical University Innsbruck, Innsbruck, Austria
Search for more papers by this authorGregor K. Wenning MD, PhD
Department of Neurology, Medical University Innsbruck, Innsbruck, Austria
Search for more papers by this authorJohn A. Hardy PhD, MD (Hon), FMedSci
Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, London, United Kingdom
Search for more papers by this authorAndrew B. Singleton PhD
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD
A.B.S. and T.G. are joint last authors.
Search for more papers by this authorThomas Gasser MD
Hertie-Institute for Clinical Brain Research, Department of Neurodegenerative Diseases, University of Tuebingen, Tuebingen, Germany
A.B.S. and T.G. are joint last authors.
Search for more papers by this authorMembers of the EMSA study group are listed in the Appendix.
Potential conflict of interest: Nothing to report.
Abstract
To test whether the synucleinopathies Parkinson's disease and multiple system atrophy (MSA) share a common genetic etiology, we performed a candidate single nucleotide polymorphism (SNP) association study of the 384 most associated SNPs in a genome-wide association study of Parkinson's disease in 413 MSA cases and 3,974 control subjects. The 10 most significant SNPs were then replicated in additional 108 MSA cases and 537 controls. SNPs at the SNCA locus were significantly associated with risk for increased risk for the development of MSA (combined p = 5.5 × 1012; odds ratio 6.2). Ann Neurol 2009;65:610–614
Supporting Information
Additional Supporting Information may be found in the online version of this article.
| Filename | Description |
|---|---|
| sm_Fig_001.doc39 KB | Supplemental Fig 1. Candidate SNP association study in multiple system atrophy (screening stage). 339 candidate SNPs were tested in 400 MSA cases and 3,891 controls. For each SNP five models were tested (genotypic, allelic, dominant, recessive, trend). On the x-axis the genomic position according to each chromosome is shown, the y-axis represents the -log10 of the pmin-value. Bonferroni correction level for multiple testing is indicated by a red horizontal line. Three SNPs (rs2856336, rs11931074, rs9480154) exceeded the Bonferroni significance threshold. |
| sm_fig_002.doc144.5 KB | Supplemental Fig 2. Power of a cohort of 108 cases and 537 controls to replicate associated loci under a recessive model assuming two-tailed alpha of 0.005 (i.e. Bonferroni threshold for significance in replication stage), population risk of 0.0001 and complete linkage disequilibrium between the genotyped SNP and the causative allele. |
| sm_table001.doc36.5 KB | Supplemental Table 1. Study cohorts for the screening and the replication stage |
| sm_table002.doc33.5 KB | Supplemental Table 2. Characteristics of studied cohorts |
| sm_table_003.doc31.5 KB | Supplemental Table 3. Primer sequences and fragment lengths |
| sm_table004.doc115.5 KB | Supplemental Table 4. Association test results for the ten most significant SNPs |
| sm_table005.doc28 KB | Supplemental Table 5. Association tests in 92 pathology-proven cases and 3,891 normal controls |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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