Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease

Parkinson's disease is a common disorder that leads to motor and cognitive disability. We performed a genome-wide association study of 2,000 individuals with Parkinson's disease (cases) and 1,986 unaffected controls from the NeuroGenetics Research Consortium (NGRC). We confirmed associatio...

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Published inNature genetics Vol. 42; no. 9; pp. 781 - 785
Main Authors Payami, Haydeh, Hamza, Taye H, Zabetian, Cyrus P, Tenesa, Albert, Laederach, Alain, Montimurro, Jennifer, Yearout, Dora, Kay, Denise M, Doheny, Kimberly F, Paschall, Justin, Pugh, Elizabeth, Kusel, Victoria I, Collura, Randall, Roberts, John, Griffith, Alida, Samii, Ali, Scott, William K, Nutt, John, Factor, Stewart A
Format Journal Article
LanguageEnglish
Published New York Nature Publishing Group US 01.09.2010
Nature Publishing Group
Subjects
631/1647/2217/2138
631/208/727/2000
692/699/375/365/1718
Adult
Age of Onset
Aged
Aged, 80 and over
Agriculture
Animal Genetics and Genomics
Antiparkinsonian agents
Biological and medical sciences
Biomedical and Life Sciences
Biomedicine
Cancer Research
Case-Control Studies
Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases
Drug therapy
Female
Fundamental and applied biological sciences. Psychology
Gene Function
Genetic aspects
Genetic Linkage
Genetic Predisposition to Disease
Genetic Variation - physiology
Genetics of eukaryotes. Biological and molecular evolution
Genome-Wide Association Study
Health aspects
Histocompatibility antigens
HLA Antigens - genetics
HLA histocompatibility antigens
Human Genetics
Humans
letter
Male
Medical sciences
Meta-Analysis as Topic
Middle Aged
Nervous system (semeiology, syndromes)
Nervous system as a whole
Neurology
Odds Ratio
Parkinson Disease - epidemiology
Parkinson Disease - genetics
Parkinson's disease
Physiological aspects
Risk factors
Single nucleotide polymorphisms
Young Adult
United States
Nervous system diseases
Late
Genetic variability
Sporadic
Genetic variant
Central nervous system disease
Parkinson disease
Degenerative disease
Cerebral disorder
Extrapyramidal syndrome
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Abstract Parkinson's disease is a common disorder that leads to motor and cognitive disability. We performed a genome-wide association study of 2,000 individuals with Parkinson's disease (cases) and 1,986 unaffected controls from the NeuroGenetics Research Consortium (NGRC). We confirmed associations with SNCA and MAPT, replicated an association with GAK (using data from the NGRC and a previous study, P = 3.2 × 10−9) and detected a new association with the HLA region (using data from the NGRC only, P = 2.9 × 10−8), which replicated in two datasets (meta-analysis P = 1.9 × 10−10). The HLA association was uniform across all genetic and environmental risk strata and was strong in sporadic (P = 5.5 × 10−10) and late-onset (P = 2.4 × 10−8) disease. The association peak we found was at rs3129882, a noncoding variant in HLA-DRA. Two studies have previously suggested that rs3129882 influences expression of HLA-DR and HLA-DQ. The brains of individuals with Parkinson's disease show upregulation of DR antigens and the presence of DR-positive reactive microglia, and nonsteroidal anti-inflammatory drugs reduce Parkinson's disease risk. The genetic association with HLA supports the involvement of the immune system in Parkinson's disease and offers new targets for drug development.
AbstractList Parkinson's disease is a common disorder that leads to motor and cognitive disability. We performed a genome-wide association study of 2,000 individuals with Parkinson's disease (cases) and 1,986 unaffected controls from the NeuroGenetics Research Consortium (NGRC). We confirmed associations with SNCA and MAPT, replicated an association with GAK (using data from the NGRC and a previous study, P = 3.2 x 10(-9)) and detected a new association with the HLA region (using data from the NGRC only, P = 2.9 x 10(-8)), which replicated in two datasets (meta-analysis P = 1.9 x 10(-10)). The HLA association was uniform across all genetic and environmental risk strata and was strong in sporadic (P = 5.5 x 10(-10)) and late-onset (P = 2.4 x 10(-8)) disease. The association peak we found was at rs3129882, a noncoding variant in HLA-DRA. Two studies have previously suggested that rs3129882 influences expression of HLA-DR and HLA-DQ. The brains of individuals with Parkinson's disease show upregulation of DR antigens and the presence of DR-positive reactive microglia, and nonsteroidal anti-inflammatory drugs reduce Parkinson's disease risk. The genetic association with HLA supports the involvement of the immune system in Parkinson's disease and offers new targets for drug development.
Parkinson's disease is a common disorder that leads to motor and cognitive disability. We performed a genome-wide association study of 2,000 individuals with Parkinson's disease (cases) and 1,986 unaffected controls from the NeuroGenetics Research Consortium (NGRC). We confirmed associations with SNCA and MAPT, replicated an association with GAK (using data from the NGRC and a previous study, P = 3.2 10 super(-9)) and detected a new association with the HLA region (using data from the NGRC only, P = 2.9 10 super(-8)), which replicated in two datasets (meta-analysis P = 1.9 10 super(-10)). The HLA association was uniform across all genetic and environmental risk strata and was strong in sporadic (P = 5.5 10 super(-10)) and late-onset (P = 2.4 10 super(-8)) disease. The association peak we found was at rs3129882, a noncoding variant in HLA-DRA. Two studies have previously suggested that rs3129882 influences expression of HLA-DR and HLA-DQ. The brains of individuals with Parkinson's disease show upregulation of DR antigens and the presence of DR-positive reactive microglia, and nonsteroidal anti-inflammatory drugs reduce Parkinson's disease risk. The genetic association with HLA supports the involvement of the immune system in Parkinson's disease and offers new targets for drug development.
Parkinson's disease is a common disorder that leads to motor and cognitive disability. We performed a genome-wide association study of 2,000 individuals with Parkinson's disease (cases) and 1,986 unaffected controls from the NeuroGenetics Research Consortium (NGRC). We confirmed associations with SNCA and MAPT, replicated an association with GAK (using data from the NGRC and a previous study, P = 3.2 x 10(-9)) and detected a new association with the HLA region (using data from the NGRC only, P = 2.9 x 10(-8)), which replicated in two datasets (meta-analysis P = 1.9 x 10(-10)). The HLA association was uniform across all genetic and environmental risk strata and was strong in sporadic (P = 5.5 x 10(-10)) and late-onset (P = 2.4 x 10(-8)) disease. The association peak we found was at rs3129882, a noncoding variant in HLA-DRA. Two studies have previously suggested that rs3129882 influences expression of HLA-DR and HLA-DQ. The brains of individuals with Parkinson's disease show upregulation of DR antigens and the presence of DR-positive reactive microglia, and nonsteroidal anti-inflammatory drugs reduce Parkinson's disease risk. The genetic association with HLA supports the involvement of the immune system in Parkinson's disease and offers new targets for drug development.Parkinson's disease is a common disorder that leads to motor and cognitive disability. We performed a genome-wide association study of 2,000 individuals with Parkinson's disease (cases) and 1,986 unaffected controls from the NeuroGenetics Research Consortium (NGRC). We confirmed associations with SNCA and MAPT, replicated an association with GAK (using data from the NGRC and a previous study, P = 3.2 x 10(-9)) and detected a new association with the HLA region (using data from the NGRC only, P = 2.9 x 10(-8)), which replicated in two datasets (meta-analysis P = 1.9 x 10(-10)). The HLA association was uniform across all genetic and environmental risk strata and was strong in sporadic (P = 5.5 x 10(-10)) and late-onset (P = 2.4 x 10(-8)) disease. The association peak we found was at rs3129882, a noncoding variant in HLA-DRA. Two studies have previously suggested that rs3129882 influences expression of HLA-DR and HLA-DQ. The brains of individuals with Parkinson's disease show upregulation of DR antigens and the presence of DR-positive reactive microglia, and nonsteroidal anti-inflammatory drugs reduce Parkinson's disease risk. The genetic association with HLA supports the involvement of the immune system in Parkinson's disease and offers new targets for drug development.
Parkinson's disease is a common disorder that leads to motor and cognitive disability. We performed a genome-wide association study of 2,000 individuals with Parkinson's disease (cases) and 1,986 unaffected controls from the NeuroGenetics Research Consortium (NGRC). We confirmed associations with SNCA and MAPT, replicated an association with GAK (using data from the NGRC and a previous study, P = 3.2 × 10−9) and detected a new association with the HLA region (using data from the NGRC only, P = 2.9 × 10−8), which replicated in two datasets (meta-analysis P = 1.9 × 10−10). The HLA association was uniform across all genetic and environmental risk strata and was strong in sporadic (P = 5.5 × 10−10) and late-onset (P = 2.4 × 10−8) disease. The association peak we found was at rs3129882, a noncoding variant in HLA-DRA. Two studies have previously suggested that rs3129882 influences expression of HLA-DR and HLA-DQ. The brains of individuals with Parkinson's disease show upregulation of DR antigens and the presence of DR-positive reactive microglia, and nonsteroidal anti-inflammatory drugs reduce Parkinson's disease risk. The genetic association with HLA supports the involvement of the immune system in Parkinson's disease and offers new targets for drug development.
Haydeh Payami and colleagues report results of a genome-wide association study for Parkinson's disease. They identify common variants in the HLA region associated with the late-onset sporadic form of the disease and replicate published associations with SNCA , MAPT and GAK . Parkinson's disease is a common disorder that leads to motor and cognitive disability. We performed a genome-wide association study of 2,000 individuals with Parkinson's disease (cases) and 1,986 unaffected controls from the NeuroGenetics Research Consortium (NGRC) 1 , 2 , 3 , 4 , 5 . We confirmed associations with SNCA 2 , 6 , 7 , 8 and MAPT 3 , 7 , 8 , 9 , replicated an association with GAK 9 (using data from the NGRC and a previous study 9 , P = 3.2 × 10 −9 ) and detected a new association with the HLA region (using data from the NGRC only, P = 2.9 × 10 −8 ), which replicated in two datasets (meta-analysis P = 1.9 × 10 −10 ). The HLA association was uniform across all genetic and environmental risk strata and was strong in sporadic ( P = 5.5 × 10 −10 ) and late-onset ( P = 2.4 × 10 −8 ) disease. The association peak we found was at rs3129882, a noncoding variant in HLA-DRA . Two studies have previously suggested that rs3129882 influences expression of HLA - DR and HLA-DQ 10 , 11 . The brains of individuals with Parkinson's disease show upregulation of DR antigens and the presence of DR-positive reactive microglia 12 , and nonsteroidal anti-inflammatory drugs reduce Parkinson's disease risk 4 , 13 . The genetic association with HLA supports the involvement of the immune system in Parkinson's disease and offers new targets for drug development.
Parkinson disease (PD) is a common disorder that leads to motor and cognitive disability. We performed a genome-wide association study (GWAS) with 2000 PD and 1986 control Caucasian subjects from NeuroGenetics Research Consortium. 1 – 5 We confirmed SNCA 2 , 6 – 8 and MAPT 3 , 7 – 9 ; replicated GAK 9 (P Pankratz+NGRC =3.2×10 −9 ); and detected a novel association with HLA (P NGRC =2.9×10 −8 ) which replicated in two datasets (P Meta-analysis =1.9×10 −10 ). We designate the new PD genes PARK17 (GAK) and PARK18 (HLA). PD- HLA association was uniform across genetic and environmental risk strata, and strong in sporadic (P=5.5×10 −10 ) and late-onset (P=2.4×10 −8 ) PD. The association peak was at rs3129882, a non-coding variant in HLA-DRA . Two studies suggested rs3129882 influences expression of HLA - DR and HLA-DQ . 10 , 11 PD brains exhibit up-regulation of DR antigens and presence of DR-positive reactive microglia. 12 Moreover, non-steroidal anti-inflammatory drugs (NSAID) reduce PD risk. 4 , 13 The genetic association with HLA coalesces the evidence for involvement of the immune system and offers new targets for drug development and pharmacogenetics.
Parkinson's disease is a common disorder that leads to motor and cognitive disability. We performed a genome-wide association study of 2,000 individuals with Parkinson's disease (cases) and 1,986 unaffected controls from the NeuroGenetics Research Consortium (NGRC) (1-5). We confirmed associations with SNCA (2,6-8) and MAPT (3,7-9), replicated an association with GAK9 (using data from the NGRC and a previous study (9), P = 3.2 x [10.sup.-9]) and detected a new association with the HLA region (using data from the NGRC only, P = 2.9 x [10.sup.-8]), which replicated in two datasets (meta-analysis P = 1.9 x [10.sup.-10]). The HLA association was uniform across all genetic and environmental risk strata and was strong in sporadic (P = 5.5 x [10.sup.-10]) and late-onset (P = 2.4 x [10.sup.-8]) disease. The association peak we found was at rs3129882, a noncoding variant in HLA-DRA. Two studies have previously suggested that rs3129882 influences expression of HLA-DR and HLA-DQ (10,11). The brains of individuals with Parkinson's disease show upregulation of DR antigens and the presence of DR-positive reactive microglia (12), and nonsteroidal anti-inflammatory drugs reduce Parkinson's disease risk (4,13). The genetic association with HLA supports the involvement of the immune system in Parkinson's disease and offers new targets for drug development.
Audience Academic
Author Montimurro, Jennifer
Payami, Haydeh
Kay, Denise M
Tenesa, Albert
Laederach, Alain
Paschall, Justin
Doheny, Kimberly F
Pugh, Elizabeth
Kusel, Victoria I
Hamza, Taye H
Factor, Stewart A
Scott, William K
Zabetian, Cyrus P
Griffith, Alida
Nutt, John
Collura, Randall
Roberts, John
Yearout, Dora
Samii, Ali
AuthorAffiliation 2 VA Puget Sound Health Care System and Department of Neurology, University of Washington, Seattle, WA, USA
3 Institute of Genetics and Molecular Medicine, University of Edinburgh, Scotland
1 New York State Department of Health Wadsworth Center, Albany, NY, USA
6 Virginia Mason Medical Center, Seattle, WA, USA
8 Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami, FL, USA
10 Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA
9 Department of Neurology, Oregon Health & Sciences University, Portland, Oregon, USA
4 Center for Inherited Disease Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA
7 Booth Gardner Parkinson’s Care Center, Evergreen Hospital Medical Center, Kirkland, WA, USA
5 NCBI, National Library of Medicine, National Institutes of Health, Bethesda, MD, USA
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– name: 4 Center for Inherited Disease Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA
– name: 7 Booth Gardner Parkinson’s Care Center, Evergreen Hospital Medical Center, Kirkland, WA, USA
– name: 6 Virginia Mason Medical Center, Seattle, WA, USA
– name: 9 Department of Neurology, Oregon Health & Sciences University, Portland, Oregon, USA
– name: 5 NCBI, National Library of Medicine, National Institutes of Health, Bethesda, MD, USA
– name: 1 New York State Department of Health Wadsworth Center, Albany, NY, USA
– name: 3 Institute of Genetics and Molecular Medicine, University of Edinburgh, Scotland
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https://www.ncbi.nlm.nih.gov/pubmed/20711177$$D View this record in MEDLINE/PubMed
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Issue 9
Keywords Nervous system diseases
Late
Genetic variability
Sporadic
Genetic variant
Central nervous system disease
Parkinson disease
Degenerative disease
Cerebral disorder
Extrapyramidal syndrome
Language English
License CC BY 4.0
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Snippet Parkinson's disease is a common disorder that leads to motor and cognitive disability. We performed a genome-wide association study of 2,000 individuals with...
Haydeh Payami and colleagues report results of a genome-wide association study for Parkinson's disease. They identify common variants in the HLA region...
Parkinson disease (PD) is a common disorder that leads to motor and cognitive disability. We performed a genome-wide association study (GWAS) with 2000 PD and...
SourceID pubmedcentral
proquest
gale
crossref
pubmed
pascalfrancis
springer
nature
SourceType Open Access Repository
Aggregation Database
Index Database
Publisher
StartPage 781
SubjectTerms 631/1647/2217/2138
631/208/727/2000
692/699/375/365/1718
Adult
Age of Onset
Aged
Aged, 80 and over
Agriculture
Animal Genetics and Genomics
Antiparkinsonian agents
Biological and medical sciences
Biomedical and Life Sciences
Biomedicine
Cancer Research
Case-Control Studies
Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases
Drug therapy
Female
Fundamental and applied biological sciences. Psychology
Gene Function
Genetic aspects
Genetic Linkage
Genetic Predisposition to Disease
Genetic Variation - physiology
Genetics of eukaryotes. Biological and molecular evolution
Genome-Wide Association Study
Health aspects
Histocompatibility antigens
HLA Antigens - genetics
HLA histocompatibility antigens
Human Genetics
Humans
letter
Male
Medical sciences
Meta-Analysis as Topic
Middle Aged
Nervous system (semeiology, syndromes)
Nervous system as a whole
Neurology
Odds Ratio
Parkinson Disease - epidemiology
Parkinson Disease - genetics
Parkinson's disease
Physiological aspects
Risk factors
Single nucleotide polymorphisms
Young Adult
Title Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease
URI http://dx.doi.org/10.1038/ng.642
https://link.springer.com/article/10.1038/ng.642
https://www.ncbi.nlm.nih.gov/pubmed/20711177
https://www.proquest.com/docview/749008304
https://search.proquest.com/docview/755132914
https://pubmed.ncbi.nlm.nih.gov/PMC2930111
Volume 42
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