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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

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
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Fig1: 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

Mentions: We observed a single structural genomic variant in a 70-year-old man with a family history of PD (1/126; 0.8 %; Fig. 1). B allele frequency and log R ratio indicate that this variant is an intra-chromosomal duplication at the SNCA locus. We did not identify this duplication, or any duplication at this locus, in control individuals. No other exonic rearrangements were observed in any PD patient in the PARK2, DJ-1 or PINK-1 loci.Fig. 1


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)

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
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig1: 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
Mentions: We observed a single structural genomic variant in a 70-year-old man with a family history of PD (1/126; 0.8 %; Fig. 1). B allele frequency and log R ratio indicate that this variant is an intra-chromosomal duplication at the SNCA locus. We did not identify this duplication, or any duplication at this locus, in control individuals. No other exonic rearrangements were observed in any PD patient in the PARK2, DJ-1 or PINK-1 loci.Fig. 1

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