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Grant Details

Grant Number: 1R01CA141668-01 Interpret this number
Primary Investigator: Foroud, Tatiana
Organization: Indiana Univ-Purdue Univ At Indianapolis
Project Title: Pd Gwas Consortium
Fiscal Year: 2009


Abstract

DESCRIPTION (provided by applicant): Parkinson disease (PD) is the second most common neurodegenerative disorder, affecting nearly 500,000 Americans. Although five genes have been identified which can directly cause PD when mutated, these genes likely contribute to disease in far fewer than 5% of all PD patients. Six Genome-Wide Association Studies (GWAS) have been or are in the process of being completed to identify common variants contributing to PD susceptibility and/or age of disease onset. There has been very limited overlap among the top SNPs or genes nominated in the four studies that have been publicly reported. At least two studies have reported support for an association with SNCA and MAPT. However, no cohesive analysis, like that proposed here, has been performed on these large GWAS studies. Based on the relative risk of PD to first degree relatives, and the numerous candidate genes that have been confirmed by multiple laboratories to have association with PD risk and age-of-onset (i.e. GBA, MAPT), it would appear highly likely that additional genes, not yet identified, must also contribute to PD susceptibility. In this application, we propose to create the PD GWAS Consortium which will collaboratively use the clinical and biological resources of the PD genetics research community to identify genes contributing to PD. The PD GWAS Consortium will consist not only of investigators from most of the groups generating PD GWAS data, but will also include investigators providing independent replication samples. This collaborative group will pursue four specific aims: 1) Perform meta and pooled analyses across the GWAS data available from six independent studies to identify the SNPs providing the strongest evidence of association with PD susceptibility (5,113 cases; 5,327 controls) and age of onset (5,113 PD cases) across studies. 2) Perform pooled analysis across the GWAS data available from five independent studies (4,670 cases; 4,884 controls) to identify copy number variants providing the strongest evidence of association with PD susceptibility and age of onset across studies. 3) Perform analyses in the five independent GWAS studies containing smoking data to test for gene x smoking interactions that may contribute to PD susceptibility or age of onset. 4) Genotype 384 SNPs in the genes of highest priority in a replication sample of 2,976 PD cases and 2,976 controls never included in a previous GWAS. The studies proposed herein will allow us to rapidly advance PD genetics, poise the field to pursue further studies of the most promising genomic variation and lead to a better understanding of the mechanisms contributing to disease risk and age of onset.



Publications

Coding and Noncoding Variation in LRRK2 and Parkinson's Disease Risk.
Authors: Lake J. , Reed X. , Langston R.G. , Nalls M.A. , Gan-Or Z. , Cookson M.R. , Singleton A.B. , Blauwendraat C. , Leonard H.L. , International Parkinson's Disease Genomics Consortium (IPDGC) .
Source: Movement disorders : official journal of the Movement Disorder Society, 2021-09-20; , .
EPub date: 2021-09-20.
PMID: 34542912
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Investigation of Autosomal Genetic Sex Differences in Parkinson's Disease.
Authors: Blauwendraat C. , Iwaki H. , Makarious M.B. , Bandres-Ciga S. , Leonard H.L. , Grenn F.P. , Lake J. , Krohn L. , Tan M. , Kim J.J. , et al. .
Source: Annals of neurology, 2021 07; 90(1), p. 35-42.
EPub date: 2021-05-24.
PMID: 33901317
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Genome-Wide Association Study Meta-Analysis for Parkinson Disease Motor Subtypes.
Authors: Alfradique-Dunham I. , Al-Ouran R. , von Coelln R. , Blauwendraat C. , Hill E. , Luo L. , Stillwell A. , Young E. , Kaw A. , Tan M. , et al. .
Source: Neurology. Genetics, 2021 Apr; 7(2), p. e557.
EPub date: 2021-01-28.
PMID: 33987465
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Heritability and genetic variance of dementia with Lewy bodies.
Authors: Guerreiro R. , Escott-Price V. , Hernandez D.G. , Kun-Rodrigues C. , Ross O.A. , Orme T. , Neto J.L. , Carmona S. , Dehghani N. , Eicher J.D. , et al. .
Source: Neurobiology of disease, 2019 07; 127, p. 492-501.
EPub date: 2019-04-03.
PMID: 30953760
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Parkinson's disease age at onset genome-wide association study: Defining heritability, genetic loci, and α-synuclein mechanisms.
Authors: Blauwendraat C. , Heilbron K. , Vallerga C.L. , Bandres-Ciga S. , von Coelln R. , Pihlstrøm L. , Simón-Sánchez J. , Schulte C. , Sharma M. , Krohn L. , et al. .
Source: Movement disorders : official journal of the Movement Disorder Society, 2019 06; 34(6), p. 866-875.
EPub date: 2019-04-07.
PMID: 30957308
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Frequency of Loss of Function Variants in LRRK2 in Parkinson Disease.
Authors: Blauwendraat C. , Reed X. , Kia D.A. , Gan-Or Z. , Lesage S. , Pihlstrøm L. , Guerreiro R. , Gibbs J.R. , Sabir M. , Ahmed S. , et al. .
Source: JAMA neurology, 2018-11-01; 75(11), p. 1416-1422.
PMID: 30039155
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Estimating the causal influence of body mass index on risk of Parkinson disease: A Mendelian randomisation study.
Authors: Noyce A.J. , Kia D.A. , Hemani G. , Nicolas A. , Price T.R. , De Pablo-Fernandez E. , Haycock P.C. , Lewis P.A. , Foltynie T. , Davey Smith G. , et al. .
Source: PLoS medicine, 2017 Jun; 14(6), p. e1002314.
EPub date: 2017-06-13.
PMID: 28609445
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Lack of evidence for a role of genetic variation in TMEM230 in the risk for Parkinson's disease in the Caucasian population.
Authors: Giri A. , Mok K.Y. , Jansen I. , Sharma M. , Tesson C. , Mangone G. , Lesage S. , Bras J.M. , Shulman J.M. , Sheerin U.M. , et al. .
Source: Neurobiology of aging, 2017 02; 50, p. 167.e11-167.e13.
EPub date: 2016-10-11.
PMID: 27818000
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Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing.
Authors: Jansen I.E. , Ye H. , Heetveld S. , Lechler M.C. , Michels H. , Seinstra R.I. , Lubbe S.J. , Drouet V. , Lesage S. , Majounie E. , et al. .
Source: Genome biology, 2017-01-30; 18(1), p. 22.
EPub date: 2017-01-30.
PMID: 28137300
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Additional rare variant analysis in Parkinson's disease cases with and without known pathogenic mutations: evidence for oligogenic inheritance.
Authors: Lubbe S.J. , Escott-Price V. , Gibbs J.R. , Nalls M.A. , Bras J. , Price T.R. , Nicolas A. , Jansen I.E. , Mok K.Y. , Pittman A.M. , et al. .
Source: Human molecular genetics, 2016-12-15; 25(24), p. 5483-5489.
PMID: 27798102
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Rare variants analysis of cutaneous malignant melanoma genes in Parkinson's disease.
Authors: Lubbe S.J. , Escott-Price V. , Brice A. , Gasser T. , Pittman A.M. , Bras J. , Hardy J. , Heutink P. , Wood N.M. , Singleton A.B. , et al. .
Source: Neurobiology of aging, 2016 12; 48, p. 222.e1-222.e7.
EPub date: 2016-07-28.
PMID: 27640074
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Is the MC1R variant p.R160W associated with Parkinson's?
Authors: Lubbe S.J. , Escott-Price V. , Brice A. , Gasser T. , Hardy J. , Heutink P. , Sharma M. , Wood N.W. , Nalls M. , Singleton A.B. , et al. .
Source: Annals of neurology, 2016 Jan; 79(1), p. 159-61.
EPub date: 2015-12-12.
PMID: 26389967
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Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease.
Authors: Nalls M.A. , Pankratz N. , Lill C.M. , Do C.B. , Hernandez D.G. , Saad M. , DeStefano A.L. , Kara E. , Bras J. , Sharma M. , et al. .
Source: Nature genetics, 2014 Sep; 46(9), p. 989-93.
EPub date: 2014-07-27.
PMID: 25064009
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Parkinson's disease in GTP cyclohydrolase 1 mutation carriers.
Authors: Mencacci N.E. , Isaias I.U. , Reich M.M. , Ganos C. , Plagnol V. , Polke J.M. , Bras J. , Hersheson J. , Stamelou M. , Pittman A.M. , et al. .
Source: Brain : a journal of neurology, 2014 Sep; 137(Pt 9), p. 2480-92.
EPub date: 2014-07-02.
PMID: 24993959
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Gene expression profiles in Parkinson disease prefrontal cortex implicate FOXO1 and genes under its transcriptional regulation.
Authors: Dumitriu A. , Latourelle J.C. , Hadzi T.C. , Pankratz N. , Garza D. , Miller J.P. , Vance J.M. , Foroud T. , Beach T.G. , Myers R.H. .
Source: PLoS genetics, 2012 Jun; 8(6), p. e1002794.
EPub date: 2012-06-28.
PMID: 22761592
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Meta-analysis of Parkinson's disease: identification of a novel locus, RIT2.
Authors: Pankratz N. , Beecham G.W. , DeStefano A.L. , Dawson T.M. , Doheny K.F. , Factor S.A. , Hamza T.H. , Hung A.Y. , Hyman B.T. , Ivinson A.J. , et al. .
Source: Annals of neurology, 2012 Mar; 71(3), p. 370-84.
PMID: 22451204
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Amyloid pathway-based candidate gene analysis of [(11)C]PiB-PET in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort.
Authors: Swaminathan S. , Shen L. , Risacher S.L. , Yoder K.K. , West J.D. , Kim S. , Nho K. , Foroud T. , Inlow M. , Potkin S.G. , et al. .
Source: Brain imaging and behavior, 2012 Mar; 6(1), p. 1-15.
PMID: 21901424
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Comprehensive research synopsis and systematic meta-analyses in Parkinson's disease genetics: The PDGene database.
Authors: Lill C.M. , Roehr J.T. , McQueen M.B. , Kavvoura F.K. , Bagade S. , Schjeide B.M. , Schjeide L.M. , Meissner E. , Zauft U. , Allen N.C. , et al. .
Source: PLoS genetics, 2012; 8(3), p. e1002548.
EPub date: 2012-03-15.
PMID: 22438815
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