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

Benitez BA, Davis AA, Jin SC, Ibanez L, Ortega-Cubero S, Pastor P, Choi J, Cooper B, Perlmutter JS, Cruchaga C - Mol Neurodegener (2016)

Bottom Line: The SNCA duplication was found in 0.8 % of familial PD patients.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, School of Medicine, Washington University, 8007, 660 South Euclid Avenue, St. Louis, MO, 63110, USA. babenitez@wustl.edu.

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.

No MeSH data available.


Related in: MedlinePlus

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
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Fig2: 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

Mentions: GBA variant carriers tend to exhibit an earlier AAO than non-carriers [25]. Thus, we tested whether GBA variants affect AAO; we found that GBA variants carriers have a earlier AAO than non-carriers (54 years. vs. 62 years.; p < 0.0001) (Fig. 2a). Interestingly, when restricted to carriers and non-carriers of p.N408M using the same model, carriers had a 5.0-year-earlier onset than non-carriers (57 years. vs. 62 years.; p = 0.006) (Fig. 2b).Fig. 2


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

Benitez BA, Davis AA, Jin SC, Ibanez L, Ortega-Cubero S, Pastor P, Choi J, Cooper B, Perlmutter JS, Cruchaga C - Mol Neurodegener (2016)

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
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4837564&req=5

Fig2: 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
Mentions: GBA variant carriers tend to exhibit an earlier AAO than non-carriers [25]. Thus, we tested whether GBA variants affect AAO; we found that GBA variants carriers have a earlier AAO than non-carriers (54 years. vs. 62 years.; p < 0.0001) (Fig. 2a). Interestingly, when restricted to carriers and non-carriers of p.N408M using the same model, carriers had a 5.0-year-earlier onset than non-carriers (57 years. vs. 62 years.; p = 0.006) (Fig. 2b).Fig. 2

Bottom Line: The SNCA duplication was found in 0.8 % of familial PD patients.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, School of Medicine, Washington University, 8007, 660 South Euclid Avenue, St. Louis, MO, 63110, USA. babenitez@wustl.edu.

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.

No MeSH data available.


Related in: MedlinePlus