Genetics of Parkinson's disease heterogeneity: A genome-wide association study of clinical subtypes

Introduction: Substantial heterogeneity between individual patients in the clinical presentation of Parkinson's disease (PD) has led to the classification of distinct PD subtypes. However, genetic susceptibility factors for specific PD subtypes are not well understood. Therefore, the present study aimed to investigate the genetics of PD heterogeneity by performing a genome-wide association study (GWAS) of PD subtypes.Methods: A total of 799 PD patients were included and classified into tremor-dominant (TD) (N = 345), akinetic-rigid (AR) (N = 227), gait-difficulty (GD) (N = 82), and mixed (MX) (N = 145) phenotypic subtypes. After array genotyping and subsequent imputation, a total of 7,918,344 variants were assessed for association with each PD subtype using logistic regression models that were adjusted for age, sex, and the top five principal components of GWAS data.Results: We identified one genome-wide significant association (P < 5 x 10(-8)), which was between the MIR3976HG rs7504760 variant and the AR subtype (Odds ratio [OR] = 6.12, P = 2.57 x 10(-8)). Suggestive associations (P < 1 x 10(-6)) were observed regarding TD for RP11-497G19.3/RP11-497G19.1 rs7304254 (OR = 3.33, P = 3.89 x 10(-7)), regarding GD for HES2 rs111473931 (OR = 3.18, P = 6.85 x 10(-7)), RP11-400D2.3/CTD-2012I17.1 rs149082205 (OR = 8.96, P = 9.08 x 10(-7)), and RN7SL408P/SGK1 rs56161738 (OR = 2.97, P = 6.19 x 10(-7)), and regarding MX for MMRN2 rs112991171 (OR = 4.98, P = 1.02 x 10(-7)).Conclusion: Our findings indicate that genetic variation may account for part of the clinical heterogeneity of PD. In particular, we found a novel genome-wide significant association between MIR3976HG variation and the AR PD subtype. Replication of these findings will be important in order to better define the genetic architecture of clinical variability in PD disease presentation.