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

Genetic Loci Genetic Predisposition to Disease Genome-Wide Association Study Humans Multifactorial Inheritance Parkinson Disease / epidemiology Polymorphism, Single Nucleotide Schizophrenia / genetics
GWAS Genetic overlap Parkinson’s disease RERE Schizophrenia ZDHHC2

Journal

Biological psychiatry
ISSN: 1873-2402
Titre abrégé: Biol Psychiatry
Pays: United States
ID NLM: 0213264

Informations de publication

Date de publication:
01 02 2021
Historique:
received: 14 03 2019
revised: 14 01 2020
accepted: 30 01 2020
pubmed: 24 3 2020
medline: 24 4 2021
entrez: 24 3 2020
Statut: ppublish

Résumé

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. 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. 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. 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.

Sections du résumé

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.

Identifiants

DOI: 10.1016/j.biopsych.2020.01.026 PMID: 32201043 PMC: PMC7416467
pubmed: 32201043
pii: S0006-3223(20)30061-5
doi: 10.1016/j.biopsych.2020.01.026
pmc: PMC7416467
mid: NIHMS1568906
pii:
doi:

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

227-235

Subventions

Organisme : NIDA NIH HHS
ID : U24 DA041147
Pays : United States
Organisme : NIDA NIH HHS
ID : U01 DA051039
Pays : United States
Organisme : NIDA NIH HHS
ID : U01 DA041093
Pays : United States
Organisme : Medical Research Council
ID : MR/L010305/1
Pays : United Kingdom
Organisme : NIDA NIH HHS
ID : U24 DA041123
Pays : United States
Organisme : NIA NIH HHS
ID : T32 AG058529
Pays : United States
Organisme : NIDA NIH HHS
ID : U01 DA041025
Pays : United States
Organisme : NIDA NIH HHS
ID : U01 DA041089
Pays : United States
Organisme : NIDA NIH HHS
ID : U01 DA041106
Pays : United States
Organisme : NIDA NIH HHS
ID : U01 DA041048
Pays : United States
Organisme : NIDA NIH HHS
ID : U01 DA041148
Pays : United States
Organisme : NIDA NIH HHS
ID : U01 DA041174
Pays : United States

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

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Auteurs

Olav B Smeland (OB)

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.

Alexey Shadrin (A)

NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.

Shahram Bahrami (S)

NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.

Iris Broce (I)

Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California.

Martin Tesli (M)

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.

Oleksandr Frei (O)

NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.

Katrine V Wirgenes (KV)

Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.

Kevin S O'Connell (KS)

NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.

Florian Krull (F)

NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.

Francesco Bettella (F)

NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.

Nils Eiel Steen (NE)

NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.

Leo Sugrue (L)

Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California.

Yunpeng Wang (Y)

Centre for Lifespan Changes in Brain and Cognition, Department of Psychology, University of Oslo, Oslo, Norway.

Per Svenningsson (P)

Clinical Neuroscience, Department of Neurology, Karolinska Institute, Stockholm, Sweden.

Manu Sharma (M)

Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tubingen, Tubingen, Germany.

Lasse Pihlstrøm (L)

Department of Neurology, Oslo University Hospital, Oslo, Norway.

Mathias Toft (M)

Department of Neurology, Oslo University Hospital, Oslo, Norway.

Michael O'Donovan (M)

MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom.

Srdjan Djurovic (S)

Department of Medical Genetics, Oslo University Hospital, Oslo, Norway; NORMENT, Department of Clinical Science, University of Bergen, Bergen, Norway.

Rahul Desikan (R)

Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California.

Anders M Dale (AM)

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.

Ole A Andreassen (OA)

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.

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Classifications MeSH

questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Locus génétiques › Genome-wide Association Analysis of...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Prédisposition génétique à une maladie › Genome-wide Association Analysis of...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Épidémiologie moléculaire › Étude d'association pangénomique › Genome-wide Association Analysis of...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Genome-wide Association Analysis of...
questionsmedicales.fr › Phénomènes génétiques › Modes de transmission héréditaire › Hérédité multifactorielle › Genome-wide Association Analysis of...
questionsmedicales.fr › Maladies du système nerveux › Maladies neurodégénératives › Maladie de Parkinson › Genome-wide Association Analysis of...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Polymorphisme génétique › Polymorphisme de nucléotide simple › Genome-wide Association Analysis of...
questionsmedicales.fr › Troubles mentaux › Schizophrénie et troubles avec traits psychotiques › Schizophrénie › Genome-wide Association Analysis of...