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

Olav B Smeland; Alexey Shadrin; Shahram Bahrami; Iris Broce; Martin Tesli; Oleksandr Frei; Katrine V Wirgenes; Kevin S O'Connell; Florian Krull; Francesco Bettella; Nils Eiel Steen; Leo Sugrue; Yunpeng Wang; Per Svenningsson; Manu Sharma; Lasse Pihlstrøm; Mathias Toft; Michael O'Donovan; Srdjan Djurovic; Rahul Desikan; Anders M Dale; Ole A Andreassen

doi:10.1016/j.biopsych.2020.01.026

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

Biol Psychiatry. 2021 Feb 1;89(3):227-235. doi: 10.1016/j.biopsych.2020.01.026. Epub 2020 Feb 8.

Authors

Olav B Smeland¹, Alexey Shadrin², Shahram Bahrami², Iris Broce³, Martin Tesli⁴, Oleksandr Frei², Katrine V Wirgenes⁵, Kevin S O'Connell², Florian Krull², Francesco Bettella², Nils Eiel Steen², Leo Sugrue³, Yunpeng Wang⁶, Per Svenningsson⁷, Manu Sharma⁸, Lasse Pihlstrøm⁹, Mathias Toft⁹, Michael O'Donovan¹⁰, Srdjan Djurovic¹¹, Rahul Desikan³, Anders M Dale¹², Ole A Andreassen¹³

Affiliations

¹ NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. Electronic address: o.b.smeland@medisin.uio.no.
² NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
³ Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California.
⁴ NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Department of Mental Health, Norwegian Institute of Public Health, Oslo, Norway.
⁵ Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
⁶ Centre for Lifespan Changes in Brain and Cognition, Department of Psychology, University of Oslo, Oslo, Norway.
⁷ Clinical Neuroscience, Department of Neurology, Karolinska Institute, Stockholm, Sweden.
⁸ Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tubingen, Tubingen, Germany.
⁹ Department of Neurology, Oslo University Hospital, Oslo, Norway.
¹⁰ MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom.
¹¹ Department of Medical Genetics, Oslo University Hospital, Oslo, Norway; NORMENT, Department of Clinical Science, University of Bergen, Bergen, Norway.
¹² Department of Cognitive Science, University of California, San Diego, La Jolla, California; Department of Neuroscience, University of California, San Diego, La Jolla, California; Department of Radiology, University of California, San Diego, La Jolla, California; Center for Multimodal Imaging and Genetics, University of California, San Diego, La Jolla, California.
¹³ NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. Electronic address: o.a.andreassen@medisin.uio.no.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Genetic Loci
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Multifactorial Inheritance
Parkinson Disease* / epidemiology
Parkinson Disease* / genetics
Polymorphism, Single Nucleotide
Schizophrenia* / genetics

Abstract

Publication types

MeSH terms

Grants and funding