Genomewide association study for susceptibility genes contributing to familial Parkinson disease

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...

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Vydáno v:	Human genetics Ročník 124; číslo 6; s. 593 - 605
Hlavní autoři:	Pankratz, Nathan, Wilk, Jemma B, Latourelle, Jeanne C, DeStefano, Anita L, Halter, Cheryl, Pugh, Elizabeth W, Doheny, Kimberly F, Gusella, James F, Nichols, William C, Foroud, Tatiana, Myers, Richard H
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	Berlin/Heidelberg Berlin/Heidelberg : Springer-Verlag 01.01.2009 Springer-Verlag Springer
Témata:	Adult Aged alpha-Synuclein - genetics Analysis Biological and medical sciences Biomedical and Life Sciences Biomedicine Case-Control Studies chromosomes Classical genetics, quantitative genetics, hybrids Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases Diacylglycerol Kinase - genetics Disease susceptibility Female Fundamental and applied biological sciences. Psychology gender Gene Function Genes Genes, Recessive Genetic aspects Genetic Predisposition to Disease Genetics of eukaryotes. Biological and molecular evolution Genomes genotyping Human Human Genetics Humans Intracellular Signaling Peptides and Proteins - genetics Logistic Models logit analysis Male Medical research Medical sciences Medicine, Experimental meta-analysis Metabolic Diseases Middle Aged Models, Genetic Molecular Medicine Nervous system (semeiology, syndromes) Nervous system as a whole Neurology Original Investigations Parkinson disease Parkinson Disease - genetics Parkinson's disease Polymorphism, Single Nucleotide Protein Serine-Threonine Kinases - genetics risk tau Proteins - genetics Parkinson Disease Genomewide Association Study Parkinson Disease Patient MAPT Region Recessive Model Nervous system diseases Familial disease Sensitivity Association Central nervous system disease Parkinson disease Genetics Degenerative disease Cerebral disorder Extrapyramidal syndrome
ISSN:	0340-6717, 1432-1203, 1432-1203
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Popis
Shrnutí:	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.
Bibliografie:	http://dx.doi.org/10.1007/s00439-008-0582-9 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 N. Pankratz and J. B. Wilk are joint first authors.
ISSN:	0340-6717 1432-1203 1432-1203
DOI:	10.1007/s00439-008-0582-9