Original Investigations

Human Genetics

, Volume 124, Issue 6, pp 593-605

Genomewide association study for susceptibility genes contributing to familial Parkinson disease

  • Nathan PankratzAffiliated withIndiana University School of Medicine
  • , Jemma B. WilkAffiliated withDepartment of Neurology, Boston University School of Medicine
  • , Jeanne C. LatourelleAffiliated withDepartment of Neurology, Boston University School of Medicine
  • , Anita L. DeStefanoAffiliated withDepartment of Neurology, Boston University School of MedicineBoston University School of Public Health
  • , Cheryl HalterAffiliated withIndiana University School of Medicine
  • , Elizabeth W. PughAffiliated withJohns Hopkins University School of Medicine
  • , Kimberly F. DohenyAffiliated withJohns Hopkins University School of Medicine
  • , James F. GusellaAffiliated withMassachusetts General Hospital and Harvard Medical School
  • , William C. NicholsAffiliated withCincinnati Children’s Hospital Medical Center
    • , Tatiana ForoudAffiliated withIndiana University School of Medicine Email author 
    • , Richard H. MyersAffiliated withDepartment of Neurology, Boston University School of Medicine Email author 
    • , The PSG—PROGENI and GenePD Investigators, Coordinators and Molecular Genetic Laboratories

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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 × 10−6; OR = 1.69). Consistent evidence of association was also observed to the chromosomal regions containing SNCA (additive model: p = 5.5 × 10−5; OR = 1.35) and MAPT (recessive model: p = 2.0 × 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 × 10−7) and the MAPT region (recessive model: p = 9.8 × 10−6; additive model: p = 4.8 × 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.