Variable Effects of PD-Risk Associated SNPs and Variants in Parkinsonism-Associated Genes on Disease Phenotype in a Community-Based Cohort

Abstract

Genetic risk factors for Parkinson's disease (PD) risk and progression have been identified from genome-wide association studies (GWAS), as well as studies of familial forms of PD, implicating common variants at more than 90 loci and pathogenic or likely pathogenic variants at 16 loci. With the goal of understanding whether genetic variants at these PD-risk loci/genes differentially contribute to individual clinical phenotypic characteristics of PD, we used structured clinical documentation tools within the electronic medical record in an effort to provide a standardized and detailed clinical phenotypic characterization at the point of care in a cohort of 856 PD patients. We analyzed common SNPs identified in previous GWAS studies, as well as low-frequency and rare variants at parkinsonism-associated genes in the MDSgene database for their association with individual clinical characteristics and test scores at baseline assessment in our community-based PD patient cohort: age at onset, disease duration, Unified Parkinson's Disease Rating Scale I-VI, cognitive status, initial and baseline motor and non-motor symptoms, complications of levodopa therapy, comorbidities and family history of neurological disease with one or more than one affected family members. We find that in most cases an individual common PD-risk SNP identified in GWAS is associated with only a single clinical feature or test score, while gene-level tests assessing low-frequency and rare variants reveal genes associated in either a unique or partially overlapping manner with the different clinical features and test scores. Protein-protein interaction network analysis of the identified genes reveals that while some of these genes are members of already identified protein networks others are not. These findings indicate that genetic risk factors for PD differentially affect the phenotypic presentation and that genes associated with PD risk are also differentially associated with individual disease phenotypic characteristics at baseline. These findings raise the intriguing possibility that different SNPs/gene effects impact discrete phenotypic characteristics. Furthermore, they support the hypothesis that different gene and protein-protein interaction networks that underlie PD risk, the PD phenotype, and the neurodegenerative process leading to the disease phenotype, and point to the significance of the genetic background on disease phenotype.

Keywords: Parkinson's disease; community cohort; gene level tests; genetic association; phenotype; protein interaction network.

Figure 1

The network shown was obtained using 0.4 as the minimum required interaction score (medium confidence). In the network, the thickness of the lines corresponds to the confidence of the interactions, the colored spheres represent the 49 proteins of the genes identified in the association analyses, and uncolored spheres represent up to 20 second-shell interactions that reveal indirect interactions among the proteins. The network contains 69 nodes and 113 edges (46 expected) with an average node degree of 3.28 and an enrichment p-value of 1.11 × 10⁻¹⁶. Sixteen nodes are unconnected to the protein-interaction network.