Genomic determinants of motor and cognitive outcomes in Parkinson's disease

Abstract

Background: Little is known regarding genetic factors associated with motor or cognitive outcomes in Parkinson's disease (PD).

Objective: To identify common genetic variants associated with motor and cognitive outcomes in PD.

Methods: The sample consisted of 443 PD cases included in the first genome-wide association study (GWAS) of PD. Methods included telephone interview assessments of motor and cognitive outcomes, a median 9 years following the initial clinical assessments. Analyses included Cox proportional hazard models to study the association of 198,345 single nucleotide polymorphisms (SNPs) with survival free of Hoehn and Yahr stage ≥ 4 (motor outcome), and either TICS-M ≤ 27 or AD-8 ≥ 2 (cognitive outcomes).

Results: The SNP rs10958605 in the C8orf4 gene had the smallest p value in analyses of the motor outcome (HR = 1.81; 95% CI = 1.42-2.31; p = 1.51 × 10(-6)). The SNP rs6482992 in the CLRN3 gene had the smallest p value in analyses of the cognitive outcome (HR = 2.03, 95% CI 1.47-2.79, p = 4.08 × 10(-6)). However, no SNP associations were significant after Bonferroni correction. The C8orf4 gene had small p values for both motor and cognitive outcomes, highlighting inflammation as a possible pathogenesis mechanism for progression in PD.

Conclusions: This study suggests that common variants in several genes may be associated with motor and cognitive outcomes in PD, with biological plausibility.

Figure 1

Genome-wide association p values. The Manhattan plot shows the p value for association of 198,345 SNPs with motor (A) and cognitive (B) outcomes in Parkinson’s disease. P values are log transformed (y axis) and plotted against chromosomal position (x axis). The red line indicates the Bonferroni-corrected significance threshold.

Figure 1

Genome-wide association p values. The Manhattan plot shows the p value for association of 198,345 SNPs with motor (A) and cognitive (B) outcomes in Parkinson’s disease. P values are log transformed (y axis) and plotted against chromosomal position (x axis). The red line indicates the Bonferroni-corrected significance threshold.