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Genome-wide association analysis of Parkinson's disease and schizophrenia reveals shared genetic architecture and identifies novel risk loci

Smeland, Olav B., Shadrin, Alexey, Bahrami, Shahram, Broce, Iris, Tesli, Martin, Frei, Oleksandr, Wirgenes, Katrine V., O'Connell, Kevin S., Krull, Florian, Bettella, Francesco, Steen, Nils Eiel, Sugrue, Leo, Wang, Yunpeng, Svenningsson, Per, Sharma, Manu, Pihlstrøm, Lasse, Toft, Mathias, O'Donovan, Michael, Djurovic, Srdjan, Desikan, Rahul, Dale, Anders M. and Andreassen, Ole A. 2021. Genome-wide association analysis of Parkinson's disease and schizophrenia reveals shared genetic architecture and identifies novel risk loci. Biological Psychiatry 89 (3) , pp. 227-235. 10.1016/j.biopsych.2020.01.026

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Abstract

Background Parkinson’s disease (PD) and schizophrenia (SCZ) are heritable brain disorders that both involve dysregulation of the dopaminergic system. Epidemiological studies have reported potential comorbidity between the disorders, and movement disturbances are common in SCZ patients before treatment with antipsychotic drugs. Despite this, little is known about shared genetic etiology between the disorders. Methods We analyzed recent large genome-wide associations studies (GWAS) on 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 nine novel PD risk loci and one novel SCZ locus at conditional FDR<0.01. Further, we identified nine genomic loci jointly associated with PD and SCZ at conjunctional FDR<0.05. 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. 65 out of 67 genes mapped to the shared loci are expressed in the human brain and show cell-type specific expression profiles. Conclusions Altogether, the study increases the 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher: Elsevier
ISSN: 0006-3223
Date of First Compliant Deposit: 13 February 2020
Date of Acceptance: 30 January 2020
Last Modified: 09 Feb 2021 18:54
URI: http://orca.cardiff.ac.uk/id/eprint/129645

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