Genome-wide Association Analysis of Parkinson's Disease and Schizophrenia Reveals Shared Genetic Architecture and Identifies Novel Risk Loci

Abstract

Background: Parkinson's disease (PD) and schizophrenia (SCZ) are heritable brain disorders that involve dysregulation of the dopaminergic system. Epidemiological studies have reported potential comorbidity between the disorders, and movement disturbances are common in patients with SCZ before treatment with antipsychotic drugs. Despite this, little is known about shared genetic etiology between the disorders.

Methods: We analyzed recent large genome-wide association studies on patients with SCZ (N = 77,096) and PD (N = 417,508) using a conditional/conjunctional false discovery rate (FDR) approach to evaluate overlap in common genetic variants and improve statistical power for genetic discovery. Using a variety of biological resources, we functionally characterized the identified genomic loci.

Results: We observed genetic enrichment in PD conditional on associations with SCZ and vice versa, indicating polygenic overlap. We then leveraged this cross-trait enrichment using conditional FDR analysis and identified 9 novel PD risk loci and 1 novel SCZ locus at conditional FDR < .01. Furthermore, we identified 9 genomic loci jointly associated with PD and SCZ at conjunctional FDR < .05. There was an even distribution of antagonistic and agonistic effect directions among the shared loci, in line with the insignificant genetic correlation between the disorders. Of 67 genes mapped to the shared loci, 65 are expressed in the human brain and show cell type-specific expression profiles.

Conclusions: Altogether, the study increases understanding of the genetic architectures underlying SCZ and PD, indicating that common molecular genetic mechanisms may contribute to overlapping pathophysiological and clinical features between the disorders.

Keywords: GWAS; Genetic overlap; Parkinson’s disease; RERE; Schizophrenia; ZDHHC2.

Figure 1.

Polygenic overlap between schizophrenia (SCZ) and Parkinson’s disease (PD). Conditional Q-Q plots of nominal versus empirical −log₁₀ p-values (corrected for inflation) in A) SCZ below the standard GWAS threshold of p<5×10⁻⁸ as a function of significance of association with PD, and B) vice versa, at the level of p ⩽ 0.1, p ⩽ 0.01, p ⩽ 0.001, respectively. The blue lines indicate all SNPs. The dashed lines indicate the null hypothesis.

Figure 2.

Common genetic variants jointly associated with schizophrenia (n=77,096) and Parkinson’s disease (n=417,508) at conjunctional false discovery rate (conjFDR) < 0.05. Manhattan plot showing the –log₁₀ transformed conjFDR values for each SNP on the y-axis and chromosomal positions along the x-axis. The dotted horizontal line represents the threshold for significant shared associations (conjFDR<0.05, i.e. −log₁₀(conjFDR)>1.3). Independent lead SNPs are encircled in black, and their nearest gene is displayed. The significant shared signals in the major histocompatibility complex region (chr6:25119106–33854733) and region 8p23.1 (chr8:8091701–11835712) are represented by one lead SNP only. Further details are provided in Table 3, and Supplemental Tables 7 and 8.