Dataset Information

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

ABSTRACT:

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.

PROVIDER: phs000126.v1.p1 | EGA |

REPOSITORIES: EGA

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Publications

Influence of heterozygosity for parkin mutation on onset age in familial Parkinson disease: the GenePD study.

Sun Mei M Latourelle Jeanne C JC Wooten G Frederick GF Lew Mark F MF Klein Christine C Shill Holly A HA Golbe Lawrence I LI Mark Margery H MH Racette Brad A BA Perlmutter Joel S JS Parsian Abbas A Guttman Mark M Nicholson Garth G Xu Gang G Wilk Jemma B JB Saint-Hilaire Marie H MH DeStefano Anita L AL Prakash Ranjana R Williamson Sally S Suchowersky Oksana O Labelle Nancy N Growdon John H JH Singer Carlos C Watts Ray L RL Goldwurm Stefano S Pezzoli Gianni G Baker Kenneth B KB Pramstaller Peter P PP Burn David J DJ Chinnery Patrick F PF Sherman Scott S Vieregge Peter P Litvan Irene I Gillis Tammy T MacDonald Marcy E ME Myers Richard H RH Gusella James F JF

Archives of neurology 20060601 6

<h4>Background</h4>The PARK2 gene at 6q26 encodes parkin, whose inactivation is implicated in an early-onset autosomal recessive form of Parkinson disease (PD).<h4>Objective</h4>To evaluate the influence of heterozygosity for parkin mutation on onset age in a sample of families with at least 2 PD-affected members.<h4>Design</h4>Clinical and genetic study.<h4>Setting</h4>Twenty collaborative clinical sites.<h4>Patients</h4>Patients with familial PD collected in the GenePD study. Studied families ...[more]

PMID: 16769863

Publication: 1/8

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Project description:Parkinson disease (PD) is a neurodegenerative disease characterized by the accumulation of alpha-synuclein (SNCA) and other proteins in aggregates termed âLewy Bodiesâ within neurons. PD has both genetic and environmental risk factors, and while processes leading to aberrant protein aggregation are unknown, past work points to abnormal levels of SNCA and other proteins. Although several genome-wide studies have been performed for PD, these have focused on DNA sequence variants by genome-wide association studies (GWAS) and on RNA levels (microarray transcriptomics), while genome-wide proteomics analysis has been lacking. After appropriate filters, proteomics identified 3,558 unique proteins and 283 of these (7.9%) were significantly different between PD and controls (q-value<0.05). RNA-sequencing identified 17,580 protein-coding genes and 1,095 of these (6.2%) were significantly different (FDR p-value<0.05), but only 166 of the FDR significant protein-coding genes (0.94%) were present among the 3,558 proteins characterized. Of these 166, eight genes (4.8%) were significant in both studies, with the same direction of effect. Functional enrichment analysis of the proteomics results strongly supports mitochondrial-related pathways, while comparable analysis of the RNA-sequencing results implicates protein folding pathways and metallothioneins. Ten of the implicated genes or proteins co-localized to GWAS loci. Evidence implicating SNCA was stronger in proteomics than in RNA-sequencing analyses. Notably, differentially expressed protein-coding genes were more likely to not be characterized in the proteomics analysis, which lessens the ability to compare across platforms. Combining multiple genome-wide platforms offers novel insights into the pathological processes responsible for this disease by identifying pathways implicated across methodologies. The study consists of mRNA-Seq (29 PD, 44 neurologically normal controls) and three-stage Mass Spectrometry Tandem Mass Tag Proteomics (12 PD, 12 neurologically normal controls) performed in post-mortem BA9 brain tissue. The proteomics samples are a subset of the RNA-Seq samples.

Dataset Information

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

Publications

Influence of heterozygosity for parkin mutation on onset age in familial Parkinson disease: the GenePD study.

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