CIDR: Genome Wide Association Study in Familial Parkinson Disease (PD)

This proposal brings together the two largest NIH funded genetic studies focused on the identification of novel genes that influence the risk of PD. These two studies, PROGENI (PI: Tatiana Foroud; R01NS037167) and GenePD (PI: Richard Myers; R01NS036711) have been evaluating and recruiting families with two or more PD affected members for more than 8 years and represent the largest such cohorts world-wide. The combined sample has more than 1,000 PD families. Each study has used rigorous clinical criteria to assess their study participants. Unlike previous genome wide association studies (GWAS) in PD, all the PD cases in this proposal have a positive family history of disease. In the vast majority of these families, the index PD case has at least one sibling with the disease. Thus, the sample is unique for having substantial evidence for a genetic contribution to disease. The control group for this study consists of samples previously collected and maintained by the NINDS Repository. Genome-wide, single nucleotide polymorphism (SNP) genotyping services were provided by the Center for Inherited Disease Research (CIDR). Data analyses will focus on the identification of SNPs associated with PD susceptibility and the age of onset of disease.]]>
PROGENI Case Report Form A Subject HistoryPROGENI Case Report Form B UPDRSPROGENI Case Report Form D Mini-Mental Status ExamPROGENI Case Report Form F Diagnostic Check SheetGenetic Linkage Study in Parkinson's Disease: Ancillary Risk Factor FormInstitutional Review BoardParkinson's Disease Genetic Study Diagnostic WorksheetGenetic Linkage Study in Parkinson's Disease: Family History QuestionnaireIUPUI and Clarian Informed Consent Statement for Parkinson's Research: The Organized Genetics Initative (PROGENI)Protocol for Parkinson Disease Collaborative Study of Genetic Linkage A.K.A. Parkinson's Research: The Organized Genetics Initiative [PROGENI]Participant Protection Policy FAQ Unlike previous studies that focused primarily on sporadic Parkinson disease (PD), we have performed the first genome-wide association study (GWAS) in familial PD. Genotyping was performed at the Center for Inherited Disease Research (CIDR) 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 (age at evaluation for controls and onset for cases). PD cases were selected from two ongoing studies of familial PD: PROGENI and GenePD. On average, each PD participant had an additional 1.8 relatives who were reported to have PD. Only a single individual per family was genotyped ensuring sample independence. PD cases underwent a uniform neurological evaluation that employed PD diagnostic criteria based broadly on the United Kingdom PD Society Brain Bank criteria. Control samples (n = 895) were obtained from the NINDS Human Genetics Resource Center at the Coriell Institute Coriell Cell Repositories. Cases were excluded from analyses if they were known to harbor a causative mutation (i.e. two parkin mutations, one LRRK2 mutation, etc.).PD Diagnostic Criteria: Both studies have employed PD diagnostic criteria based broadly on the United Kingdom PD Society Brain Bank Criteria [Gibb and Lees 1988]. While each study has slightly modified these criteria, the diagnostic criteria from the two studies are compatible and similar enough to allow the PD samples from the two studies to be combined. Control Samples: Control samples were obtained from the NINDS Repository and include only Caucasian, non-Hispanic subjects. They all are negative for neurological disease based on self-report. They do not have a family history of any neurodegenerative disease.]]>
These two studies of familial PD have been ongoing for nearly a decade. They have each actively ascertained families with PD and used rigorous clinical criteria to assess their study participants. Subjects have been recruited through international collaborations, although both studies have primarily recruited Caucasian subjects. Each study has completed extensive genetic analyses to elucidate the role of recently identified genes such as parkin and LRRK2, as well as to identify novel genetic risk factors. In addition, both studies have performed whole genome linkage studies which have detected evidence of specific chromosomal regions influencing PD risk. Thus, a GWA study using the combined samples from each study has the potential to maximize the power to detect genetic risk factors of relatively small effect size.]]>