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      Genome-Wide Association Study reveals genetic risk underlying Parkinson’s disease

      research-article
      Author(s): 1 , 2 , 3 , 1 , 4 , 3 , 1 , 5 , 3 , 5 , 6 , 1 , 5 , 1 , 5 , 3 , 1 , 7 , 8 , 8 , 9 , 1 , 10 , 10 , 5 , 11 , 12 , 1 , 12 , 12 , 1 , 13 , 1 , 1 , 14 , 1 , 15 , 16 , 16 , 16 , 17 , 18 , 19 , 5 , 20 , 20 , 18 , 9 , 4 , 1 , 3
      Publication date (Electronic):
      Journal: Nature genetics

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          Abstract

          We performed a genome-wide association study (GWAS) in 1,713 Caucasian patients with Parkinson’s disease (PD) and 3,978 controls. After replication in 3,361 cases and 4,573 controls, two strong association signals were observed: in the α-synuclein gene( SNCA) (rs2736990, OR=1.23, p=2.24×10 −16) and at the MAPT locus (rs393152, OR=0.77, p=1.95×10 −16). We exchanged data with colleagues performing a GWAS in Asian PD cases. Association at SNCA was replicated in the Asian GWAS 1, confirming this as a major risk locus across populations. We were able to replicate the effect of a novel locus detected in the Asian cohort ( PARK16, rs823128, OR=0.66, p=7.29×10 −8) and provide evidence supporting the role of common variability around LRRK2 in modulating risk for PD (rs1491923, OR=1.14, p=1.55×10 −5). These data demonstrate an unequivocal role for common genetic variability in the etiology of typical PD and suggest population specific genetic heterogeneity in this disease.

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          Most cited references11

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          Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases.

          A J Hughes, S Daniel, L Kilford … (1992)
          Few detailed clinico-pathological correlations of Parkinson's disease have been published. The pathological findings in 100 patients diagnosed prospectively by a group of consultant neurologists as having idiopathic Parkinson's disease are reported. Seventy six had nigral Lewy bodies, and in all of these Lewy bodies were also found in the cerebral cortex. In 24 cases without Lewy bodies, diagnoses included progressive supranuclear palsy, multiple system atrophy, Alzheimer's disease, Alzheimer-type pathology, and basal ganglia vascular disease. The retrospective application of recommended diagnostic criteria improved the diagnostic accuracy to 82%. These observations call into question current concepts of Parkinson's disease as a single distinct morbid entity.
          Article 0 comments Cited 1164 times – based on 0 reviews     Review now
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            Genomewide association study for susceptibility genes contributing to familial Parkinson disease.

            Judith Myers, Christopher W. Pugh, Jemma B Wilk … (2008)
            Five genes have been identified that contribute to Mendelian forms of Parkinson disease (PD); however, mutations have been found in fewer than 5% of patients, suggesting that additional genes contribute to disease risk. Unlike previous studies that focused primarily on sporadic PD, we have performed the first genomewide association study (GWAS) in familial PD. Genotyping was performed with the Illumina HumanCNV370Duo array in 857 familial PD cases and 867 controls. A logistic model was employed to test for association under additive and recessive modes of inheritance after adjusting for gender and age. No result met genomewide significance based on a conservative Bonferroni correction. The strongest association result was with SNPs in the GAK/DGKQ region on chromosome 4 (additive model: p = 3.4 x 10(-6); OR = 1.69). Consistent evidence of association was also observed to the chromosomal regions containing SNCA (additive model: p = 5.5 x 10(-5); OR = 1.35) and MAPT (recessive model: p = 2.0 x 10(-5); OR = 0.56). Both of these genes have been implicated previously in PD susceptibility; however, neither was identified in previous GWAS studies of PD. Meta-analysis was performed using data from a previous case-control GWAS, and yielded improved p values for several regions, including GAK/DGKQ (additive model: p = 2.5 x 10(-7)) and the MAPT region (recessive model: p = 9.8 x 10(-6); additive model: p = 4.8 x 10(-5)). These data suggest the identification of new susceptibility alleles for PD in the GAK/DGKQ region, and also provide further support for the role of SNCA and MAPT in PD susceptibility.
            Article 0 comments Cited 143 times – based on 0 reviews     Review now
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              Association of an extended haplotype in the tau gene with progressive supranuclear palsy.

              H. Houlden, T Lynch, L Castrillón … (1999)
              We describe two extended haplotypes that cover the human tau gene. In a total of approximately 200 unrelated caucasian individuals there is complete disequilibrium between polymorphisms which span the gene (which covers approximately 100 kb of DNA). This suggests that the establishment of the two haplotypes was an ancient event and either that recombination is suppressed in this region, or that recombinant genes are selected against. Furthermore, we show that the more common haplotype (H1) is significantly over-represented in patients with progressive supranuclear palsy (PSP), extending earlier reports of an association between an intronic dinucleotide polymorphism and PSP.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 9216904
                Journal ID (pubmed-jr-id): 2419
                Journal ID (nlm-ta): Nat Genet
                Title: Nature genetics
                ISSN (Print): 1061-4036
                ISSN (Electronic): 1546-1718
                Publication date Nihms-submitted: 27 October 2009
                Publication date (Electronic): 15 November 2009
                Publication date (Print): December 2009
                Publication date PMC-release: 1 June 2010
                Volume: 41
                Issue: 12
                Pages: 1308-1312
                Affiliations
                [1 ]Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA
                [2 ]Department of Clinical Genetics Section of Medical Genomics VU Medical Center De Boelelaan 1085 1081 Amsterdam, the Netherlands
                [3 ]Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tubingen, and German Center for Neurodegenerative Diseases, Tubingen, Germany
                [4 ]Center for Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal
                [5 ]Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, London, United Kingdom
                [6 ]Institute of Human Genetics, Helmholtz Zentrum Munchen, German Research Centre for Environmental Health, Neuherberg, Germany
                [7 ]Section of Clinical and Molecular Neurogenetics at the Department of Neurology, University of Luebeck, Germany
                [8 ]Department of Psychiatry; Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA
                [9 ]Department of Medical Genetics, Institute of Human Genetics, University of Tubingen, Tubingen, Germany
                [10 ]Institute of Epidemiology, Helmholtz Zentrum Munchen, German Research Centre for Environmental Health, Neuherberg, Germany
                [11 ]Institute of Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany
                [12 ]Movement Disorders Center, University of Florida, Gainesville, Florida, USA
                [13 ]Institut fur Klinische Molekularbiologie, Christian-Albrechts-Universitat Kiel, Germany
                [14 ]Department of Molecular and Human Genetics, Baylor College of Medicine, Texas, USA
                [15 ]Parkinson’s disease clinic, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA
                [16 ]Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA
                [17 ]AARP, Washington DC, USA
                [18 ]Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, North Carolina, USA
                [19 ]Departments of Neurology, Radiology, Neurosurgery, Pharmacology, Kinesiology & Bioengineering, Pennsylvania State University-Milton S. Hershey Medical Center, Hershey, Pennsylvania, USA
                [20 ]Klinik fur Neurologie, UK-SH, Campus Kiel, Christian-Albrechts-Universitat Kiel, Kiel, Germany
                Author notes
                [CA ]Please address correspondence to Dr. Thomas Gasser ( thomas.gasser@ 123456uni-tuebingen.de ) and Dr. Andrew Singleton ( singleta@ 123456mail.nih.gov )
                [#]

                these authors contributed equally

                Article
                Manuscript ID: nihpa154602
                DOI: 10.1038/ng.487
                PMC ID: 2787725
                PubMed ID: 19915575
                SO-VID: c4d238a0-32eb-427e-8a18-9a3dbd37ee98
                License:

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Funding
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Funded by: National Institute on Aging : NIA
                Award ID: R01 NS058714-03 ||NS
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Funded by: National Institute on Aging : NIA
                Award ID: R01 NS050425-05 ||NS
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Funded by: National Institute on Aging : NIA
                Award ID: R01 NS041509-09 ||NS
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Funded by: National Institute on Aging : NIA
                Award ID: Z01 AG000949-03 ||AG
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                Subject: Article

                ScienceOpen disciplines: Genetics
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                ScienceOpen disciplines: Genetics

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