Impact of Parkinson's disease risk loci on age at onset

Abstract

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.

Keywords: DGKQ; GAK; GBA; N370S; Parkinson's disease, PD; age at onset; genetic association; genetic risk score; genome-wide association study, GWAS.