Resequencing analysis of five Mendelian genes and the top genes from genome-wide association studies in Parkinson's Disease.
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.
Department of Internal Medicine, School of Medicine, Washington University, 8007, 660 South Euclid Avenue, St. Louis, MO, 63110, USA. babenitez@wustl.edu.
Bruno A
BA
Benitez
Department of Neurology, School of Medicine, Washington University, St. Louis, MO, USA.
Albert A
AA
Davis
Department of Psychiatry, School of Medicine, Washington University, St. Louis, MO, USA.
Sheng Chih
SC
Jin
Department of Psychiatry, School of Medicine, Washington University, St. Louis, MO, USA.
Laura
L
Ibanez
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.
Sara
S
Ortega-Cubero
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.
Pau
P
Pastor
Department of Psychiatry, School of Medicine, Washington University, St. Louis, MO, USA.
Jiyoon
J
Choi
Department of Psychiatry, School of Medicine, Washington University, St. Louis, MO, USA.
Breanna
B
Cooper
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.
Joel S
JS
Perlmutter
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.
Carlos
C
Cruchaga
D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D055106:Genome-Wide Association Study; D005962:Glucosylceramidase / Q000235:genetics; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics*; D011494:Protein Kinases / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D051844:alpha-Synuclein / Q000235:genetics; D000099202:PTEN-Induced Putative Kinase
D005962:Glucosylceramidase; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D051844:alpha-Synuclein; D000099202:PTEN-Induced Putative Kinase; C497604:SNCA protein, human; C495280:LRRK2 protein, human
Association study; DJ-1; GBA rare variants, gene-based analysis; LRRK2; MAPT; PARKIN; PINK1; Parkinson’s; SNCA