Impact of Parkinson's disease risk loci on age at onset.
BACKGROUND
The aim of this study was to assess whether recently identified Parkinson's disease (PD) risk genes also influence age at onset in PD.


METHODS
We genotyped 23 single-nucleotide polymorphisms in 1,526 Danish PD patients and performed linear regression analyses with age at onset. The combined impact of PD risk loci on age at onset was assessed by linear regression analyses using a weighted genetic risk score.


RESULTS
The strongest effects were observed with rs12726330 in GBA (beta = -3.63, P = 2.0 × 10(-5) ) and rs34311866 in TMEM175/GAK (beta = -1.19, P = 4.0 × 10(-3) ), corresponding to a 3.6-y and 1.2-y decrease of age at onset per risk allele, respectively. The weighted genetic risk score yielded significant association with reduced onset age (P = 3.98 × 10(-3) ), although the variance explained was small (0.6%), and the effect was mostly driven by polymorphisms in GBA and TMEM175/GAK.


CONCLUSIONS
Overall, our study indicates that GBA and TMEM175/GAK significantly alter age at onset in PD.
Platform for Genome Analytics, Institutes of Neurogenetics & Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany.
Christina M
CM
Lill
Institute of Cancer Epidemiology, Danish Cancer Society Research Center, Copenhagen, Denmark.|Department of Epidemiology and Environmental Sciences, School of Public Health, University of California, Los Angeles, California, USA.
Johnni
J
Hansen
Institute of Cancer Epidemiology, Danish Cancer Society Research Center, Copenhagen, Denmark.
Jørgen H
JH
Olsen
Institute for Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center Mainz, Mainz, Germany.
Harald
H
Binder
Department of Epidemiology and Environmental Sciences, School of Public Health, University of California, Los Angeles, California, USA.
Beate
B
Ritz
Platform for Genome Analytics, Institutes of Neurogenetics & Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany.|School of Public Health, Faculty of Medicine, The Imperial College of Science, Technology, and Medicine, London, UK.
Lars
L
Bertram
D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D003718:Denmark; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D015221:Potassium Channels / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012307:Risk Factors; D001617:beta-Glucosidase / Q000235:genetics*
D047908:Intracellular Signaling Peptides and Proteins; D015221:Potassium Channels; C000602835:TMEM175 protein, human; C486325:GAK protein, human; D017346:Protein Serine-Threonine Kinases; D001617:beta-Glucosidase
DGKQ; GAK; GBA; N370S; Parkinson's disease, PD; age at onset; genetic association; genetic risk score; genome-wide association study, GWAS