☆ 4.7 Article

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

BIOLOGICAL PSYCHIATRY (2021)

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Journal

BIOLOGICAL PSYCHIATRY
Volume 89, Issue 3, Pages 227-235

Publisher

ELSEVIER SCIENCE INC
DOI: 10.1016/j.biopsych.2020.01.026

Keywords

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Categories

Neurosciences Psychiatry

Funding

  1. Research Council of Norway [262656, 249711, 248980, 248778, 226971, 223273]
  2. South-East Norway Regional Health Authority [2016-064]
  3. K.G. Jebsen Stiftelsen [SKGJ-MED-008]
  4. National Institutes of Health [U24DA041123]
  5. General Electric Healthcare

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The study reveals genetic overlap between PD and SCZ, identifying novel risk loci and shared genomic loci. These findings suggest common molecular mechanisms contributing to overlap in pathophysiological and clinical features between the disorders.
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.

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