Resequencing analysis of five Mendelian genes and the top genes from genome-wide association studies in Parkinson's Disease.

Bruno A Benitez,Joel S Perlmutter,Joel S Perlmutter,Breanna Cooper,Pau Pastor,Sara Ortega-Cubero,Carlos Cruchaga,Carlos Cruchaga,Sara Ortega-Cubero,Sheng Chih Jin,Jiyoon Choi,Sara Ortega-Cubero,Sara Ortega-Cubero,Albert A Davis,Laura Ibanez

doi:10.1186/s13024-016-0097-0

Abstract

BackgroundMost sequencing studies in Parkinson’s disease (PD) have focused on either a particular gene, primarily in familial and early onset PD samples, or on screening single variants in sporadic PD cases. To date, there is no systematic study that sequences the most common PD causing genes with Mendelian inheritance [α-synuclein (SNCA), leucine-rich repeat kinase 2 (LRRK2), PARKIN, PTEN-induced putative kinase 1 (PINK1) and DJ-1 (Daisuke-Junko-1)] and susceptibility genes [glucocerebrosidase beta acid (GBA) and microtubule-associated protein tau (MAPT)] identified through genome-wide association studies (GWAS) in a European-American case-control sample (n=815).ResultsDisease-causing variants in the SNCA,LRRK2 and PARK2 genes were found in 2 % of PD patients. The LRRK2, p.G2019S mutation was found in 0.6 % of sporadic PD and 4.8 % of familial PD cases. Gene-based analysis suggests that additional variants in the LRRK2 gene also contribute to PD risk. The SNCA duplication was found in 0.8 % of familial PD patients. Novel variants were found in 0.8 % of PD cases and 0.6 % of controls. Heterozygous Gaucher disease-causing mutations in the GBA gene were found in 7.1 % of PD patients. Here, we established that the GBA variant (p.T408M) is associated with PD risk and age at onset. Additionally, gene-based and single-variant analyses demostrated that GBA gene variants (p.L483P, p.R83C, p.N409S, p.H294Q and p.E365K) increase PD risk.ConclusionsOur data suggest that the impact of additional untested coding variants in the GBA and LRRK2 genes is higher than previously estimated. Our data also provide compelling evidence of the existence of additional untested variants in the primary Mendelian and PD GWAS genes that contribute to the genetic etiology of sporadic PD.

Highlights

Most sequencing studies in Parkinson’s disease (PD) have focused on either a particular gene, primarily in familial and early onset PD samples, or on screening single variants in sporadic PD cases
We performed pooled DNA-targeted deep-sequencing of the protein-coding regions of 7 genes, including 5 genes previously reported to most frequently cause familial forms of PD (SNCA, leucine-rich repeat kinase 2 (LRRK2), DJ-1, PARK2 and PTEN-induced putative kinase 1 (PINK1)) and 2 genes that have significant associations in genome-wide association studies (GWAS) with sporadic PD (GBA and microtubule-associated protein tau (MAPT) genes) in 478 PD patients and 337 healthy individuals of
We found a significant enrichment of coding variants in the LRRK2 gene in PD cases compared to controls (p = 0.01, odd ratio (OR) = 1.86, 95 % confidence interval (CI) = 1.14-3.02) (Table 6), which suggests that there are other risk variants in the LRRK2 gene in addition to the known pathogenic p.G2019S mutation

Summary

Introduction

Most sequencing studies in Parkinson’s disease (PD) have focused on either a particular gene, primarily in familial and early onset PD samples, or on screening single variants in sporadic PD cases. Benitez et al Molecular Neurodegeneration (2016) 11:29 provide unequivocal, compelling evidence for the existence of undiscovered genetic factors that contribute to the etiology of PD. Both candidate gene association studies and GWAS repeatedly validate that the most statistically significant signals associated with PD are common variants located close to SNCA, LRRK2, MAPT genes and low frequency coding variants in the GBA gene [2, 4, 7, 10, 13,14,15,16]. Deep-sequencing LRRK2 and GBA genes can identify additional untested coding risk variants and protective alleles, as previously reported in these genes [17]

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Results

Discussion

Conclusion