The multi-modality neuroimaging analysis identified an essential genetic variant associated with Parkinson's disease

Over 90 genetic variants have been found to be associated with Parkinson's disease (PD) in genome-wide association studies, however, the neural mechanisms of these identified genetic variants conferring risk of PD were largely unexplored. The objective of this study was to identify essential genetic variants in PD for future functional and mechanistic studies. We revealed 14 single nucleotide polymorphisms (SNPs) conferring risk of PD were significantly correlated with brain gene expressions. Although they were not significantly associated with the clinical presentations of PD patients in multivariate regression models, multi-SNP models constructed by several genetic variants powerfully predicted clinical presentations of PD patients. Among 14 SNPs, GPNMB rs199347 significantly modifies the activity of sensorimotor network (adjusted p < 0.0007, FDR corrected) after adjusting age, sex, disease duration, and the genotypes of remaining 13 SNPs. Graph-based network analysis further demonstrated that GPNMB rs199347 had remarkable effects on the global topology of functional network and specifically shaped the nodal network metrics of bilateral caudate. GPNMB rs199347 was not associated with significant changes of structural network metrics. Our findings support that GPNMB rs199347 is an essential genetic variant specifically shaping functional network of PD patients.