Dataset Information

The heritability of risk and age at onset of Parkinson's disease after accounting for known genetic risk factors.

ABSTRACT: We questioned whether the evidence for the genetic component in Parkinson's disease (PD) in Caucasians could be explained by the causative and susceptibility genes that have already been identified. We estimated heritability of risk and age at onset of PD in a well-characterized sample of 504 nuclear families (2828 individuals). After excluding families with known pathogenic mutations and accounting for the major susceptibility genes, the heritability of risk of developing PD was 0.41 (P=0.01). These data suggest that approximately 40% of the variation in susceptibility to PD is due to as-yet unidentified genes, the remainder is likely environmental.

SUBMITTER: Hamza TH

PROVIDER: S-EPMC2947819 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The heritability of risk and age at onset of Parkinson's disease after accounting for known genetic risk factors.

Hamza Taye H TH Payami Haydeh H

Journal of human genetics 20100305 4

We questioned whether the evidence for the genetic component in Parkinson's disease (PD) in Caucasians could be explained by the causative and susceptibility genes that have already been identified. We estimated heritability of risk and age at onset of PD in a well-characterized sample of 504 nuclear families (2828 individuals). After excluding families with known pathogenic mutations and accounting for the major susceptibility genes, the heritability of risk of developing PD was 0.41 (P=0.01). ...[more]

PMID: 20203693

Similar Datasets

Project description:Parkinson's disease is a genetically complex disorder. Multiple genes have been shown to contribute to the risk of Parkinson's disease, and currently 90 independent risk variants have been identified by genome-wide association studies. Thus far, a number of genes (including SNCA, LRRK2, and GBA) have been shown to contain variability across a spectrum of frequency and effect, from rare, highly penetrant variants to common risk alleles with small effect sizes. Variants in GBA, encoding the enzyme glucocerebrosidase, are associated with Lewy body diseases such as Parkinson's disease and Lewy body dementia. These variants, which reduce or abolish enzymatic activity, confer a spectrum of disease risk, from 1.4- to >10-fold. An outstanding question in the field is what other genetic factors that influence GBA-associated risk for disease, and whether these overlap with known Parkinson's disease risk variants. Using multiple, large case-control datasets, totalling 217 165 individuals (22 757 Parkinson's disease cases, 13 431 Parkinson's disease proxy cases, 622 Lewy body dementia cases and 180 355 controls), we identified 1691 Parkinson's disease cases, 81 Lewy body dementia cases, 711 proxy cases and 7624 controls with a GBA variant (p.E326K, p.T369M or p.N370S). We performed a genome-wide association study and analysed the most recent Parkinson's disease-associated genetic risk score to detect genetic influences on GBA risk and age at onset. We attempted to replicate our findings in two independent datasets, including the personal genetics company 23andMe, Inc. and whole-genome sequencing data. Our analysis showed that the overall Parkinson's disease genetic risk score modifies risk for disease and decreases age at onset in carriers of GBA variants. Notably, this effect was consistent across all tested GBA risk variants. Dissecting this signal demonstrated that variants in close proximity to SNCA and CTSB (encoding cathepsin B) are the most significant contributors. Risk variants in the CTSB locus were identified to decrease mRNA expression of CTSB. Additional analyses suggest a possible genetic interaction between GBA and CTSB and GBA p.N370S induced pluripotent cell-derived neurons were shown to have decreased cathepsin B expression compared to controls. These data provide a genetic basis for modification of GBA-associated Parkinson's disease risk and age at onset, although the total contribution of common genetics variants is not large. We further demonstrate that common variability at genes implicated in lysosomal function exerts the largest effect on GBA associated risk for disease. Further, these results have implications for selection of GBA carriers for therapeutic interventions.

Dataset Information

The heritability of risk and age at onset of Parkinson's disease after accounting for known genetic risk factors.

Publications

The heritability of risk and age at onset of Parkinson's disease after accounting for known genetic risk factors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets