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Resequencing analysis of five Mendelian genes and the top genes from genome-wide association studies in Parkinson's Disease.
Mol Neurodegener. 2016 Apr 19; 11:29.MN

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.

Authors+Show Affiliations

Department of Internal Medicine, School of Medicine, Washington University, 8007, 660 South Euclid Avenue, St. Louis, MO, 63110, USA. babenitez@wustl.edu.Department of Neurology, School of Medicine, Washington University, St. Louis, MO, USA.Department of Psychiatry, School of Medicine, Washington University, St. Louis, MO, USA.Department of Psychiatry, School of Medicine, Washington University, St. Louis, MO, USA.Department of Neurology, Complejo Asistencial Universitario de Palencia, Palencia, Spain. Center for Applied Medical Research (CIMA) University of Navarra School of Medicine, Pamplona, Spain and Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.Center for Applied Medical Research (CIMA) University of Navarra School of Medicine, Pamplona, Spain and Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. Movement Disorders Unit, Department of Neurology, University Hospital Mutua de Terrassa, University of Barcelona, Terrassa, Barcelona, Spain.Department of Psychiatry, School of Medicine, Washington University, St. Louis, MO, USA.Department of Psychiatry, School of Medicine, Washington University, St. Louis, MO, USA.Department of Neurology, School of Medicine, Washington University, St. Louis, MO, USA. Department of Radiology, Anatomy & Neurobiology, Program in Occupational Therapy, Program in Physical Therapy, Washington University, St. Louis, MO, USA. Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University, St. Louis, MO, USA.Department of Psychiatry, School of Medicine, Washington University, St. Louis, MO, USA. Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University, St. Louis, MO, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27094865

Citation

Benitez, Bruno A., et al. "Resequencing Analysis of Five Mendelian Genes and the Top Genes From Genome-wide Association Studies in Parkinson's Disease." Molecular Neurodegeneration, vol. 11, 2016, p. 29.
Benitez BA, Davis AA, Jin SC, et al. Resequencing analysis of five Mendelian genes and the top genes from genome-wide association studies in Parkinson's Disease. Mol Neurodegener. 2016;11:29.
Benitez, B. A., Davis, A. A., Jin, S. C., Ibanez, L., Ortega-Cubero, S., Pastor, P., Choi, J., Cooper, B., Perlmutter, J. S., & Cruchaga, C. (2016). Resequencing analysis of five Mendelian genes and the top genes from genome-wide association studies in Parkinson's Disease. Molecular Neurodegeneration, 11, 29. https://doi.org/10.1186/s13024-016-0097-0
Benitez BA, et al. Resequencing Analysis of Five Mendelian Genes and the Top Genes From Genome-wide Association Studies in Parkinson's Disease. Mol Neurodegener. 2016 Apr 19;11:29. PubMed PMID: 27094865.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Resequencing analysis of five Mendelian genes and the top genes from genome-wide association studies in Parkinson's Disease. AU - Benitez,Bruno A, AU - Davis,Albert A, AU - Jin,Sheng Chih, AU - Ibanez,Laura, AU - Ortega-Cubero,Sara, AU - Pastor,Pau, AU - Choi,Jiyoon, AU - Cooper,Breanna, AU - Perlmutter,Joel S, AU - Cruchaga,Carlos, Y1 - 2016/04/19/ PY - 2015/10/20/received PY - 2016/04/14/accepted PY - 2016/4/21/entrez PY - 2016/4/21/pubmed PY - 2016/11/9/medline KW - Association study KW - DJ-1 KW - GBA rare variants, gene-based analysis KW - LRRK2 KW - MAPT KW - PARKIN KW - PINK1 KW - Parkinson’s KW - SNCA SP - 29 EP - 29 JF - Molecular neurodegeneration JO - Mol Neurodegener VL - 11 N2 - 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. SN - 1750-1326 UR - https://www.unboundmedicine.com/medline/citation/27094865/Resequencing_analysis_of_five_Mendelian_genes_and_the_top_genes_from_genome_wide_association_studies_in_Parkinson's_Disease_ L2 - https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-016-0097-0 DB - PRIME DP - Unbound Medicine ER -