title: Genomewide association study for susceptibility genes contributing to familial Parkinson disease.
abstract: 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.
authors.affiliation: Indiana University School of Medicine, Health Information and Translational Sciences Building, Indianapolis, IN 46202-3002, USA. npankrat@iupui.edu
authors.forename: Nathan
authors.initials: N
authors.lastname: Pankratz
authors.forename: Jemma B
authors.initials: JB
authors.lastname: Wilk
authors.forename: Jeanne C
authors.initials: JC
authors.lastname: Latourelle
authors.forename: Anita L
authors.initials: AL
authors.lastname: DeStefano
authors.forename: Cheryl
authors.initials: C
authors.lastname: Halter
authors.forename: Elizabeth W
authors.initials: EW
authors.lastname: Pugh
authors.forename: Kimberly F
authors.initials: KF
authors.lastname: Doheny
authors.forename: James F
authors.initials: JF
authors.lastname: Gusella
authors.forename: William C
authors.initials: WC
authors.lastname: Nichols
authors.forename: Tatiana
authors.initials: T
authors.lastname: Foroud
authors.forename: Richard H
authors.initials: RH
authors.lastname: Myers
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D019852:Diacylglycerol Kinase / Q000235:genetics; D005260:Female; D005808:Genes, Recessive; D020022:Genetic Predisposition to Disease; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D010300:Parkinson Disease / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D051844:alpha-Synuclein / Q000235:genetics; D016875:tau Proteins / Q000235:genetics
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C054369:MAPT protein, human; C497604:SNCA protein, human; D051844:alpha-Synuclein; D016875:tau Proteins; D019852:Diacylglycerol Kinase; C486325:GAK protein, human; D017346:Protein Serine-Threonine Kinases