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

Abstract

Background: 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. 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).

Results: Disease-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.

Conclusions: Our 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.

Keywords: Association study; DJ-1; GBA rare variants, gene-based analysis; LRRK2; MAPT; PARKIN; PINK1; Parkinson’s; SNCA.

Fig. 1

SNCA duplication. The lower panel shows genotyping data from PD patient, generated using NeuroXchip. Shown is B Allele frequency for each single-nucleotide polymorphism (SNP) assayed, in which a value of 0 indicates a homozygous A/A genotype, a value of 1 indicates a homozygous B/B genotype, and a value of 0.5 represents a heterozygous A/B genotype. The highlighted region (pink) delimits the duplicated segment; within this region are a lack of heterozygous calls and clusters of points at a B allele frequency of ∼ 0.33 and ∼ 0.66, which, coupled with an increased log R ratio (upper panel), are indicative of A/A/B and A/B/B genotype calls, respectively. Figure plotted using R

Fig. 2

a. Cumulative incidence rates of PD among carriers and non-carriers of all GBA variants. b. Cumulative incidence rates of PD among carriers and non-carriers of the p.N408M variant. Survival fractions were calculated using the Kaplan-Meier method and significant differences were calculated by Log-rank test