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

被引：60

作者：

Smeland, Olav B. ^{[1
,3
]}

Shadrin, Alexey ^{[1
]}

Bahrami, Shahram ^{[1
]}

Broce, Iris ^{[8
]}

Tesli, Martin ^{[1
,3
,6
]}

Frei, Oleksandr ^{[1
,3
]}

Wirgenes, Katrine, V ^{[4
]}

O'Connell, Kevin S. ^{[1
,3
]}

Krull, Florian ^{[1
,3
]}

Bettella, Francesco ^{[1
,3
]}

Steen, Nils Eiel ^{[1
,3
]}

Sugrue, Leo ^{[8
]}

Wang, Yunpeng ^{[2
]}

Svenningsson, Per ^{[13
]}

Sharma, Manu ^{[14
]}

Pihlstrom, Lasse ^{[5
]}

Toft, Mathias ^{[5
]}

O'Donovan, Michael ^{[15
]}

Djurovic, Srdjan ^{[4
,7
]}

Desikan, Rahul ^{[8
]}

Dale, Anders M. ^{[9
,10
,11
,12
]}

Andreassen, Ole A. ^{[1
,3
]}

机构：

[1] Univ Oslo, Inst Clin Med, NORMENT, Oslo, Norway

[2] Univ Oslo, Ctr Lifespan Changes Brain & Cognit, Dept Psychol, Oslo, Norway

[3] Oslo Univ Hosp, Div Mental Hlth & Addict, Oslo, Norway

[4] Oslo Univ Hosp, Dept Med Genet, Oslo, Norway

[5] Oslo Univ Hosp, Dept Neurol, Oslo, Norway

[6] Norwegian Inst Publ Hlth, Dept Mental Hlth, Oslo, Norway

[7] Univ Bergen, Dept Clin Sci, NORMENT, Bergen, Norway

[8] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, Neuroradiol Sect, San Francisco, CA 94143 USA

[9] Univ Calif San Diego, Dept Cognit Sci, La Jolla, CA 92093 USA

[10] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA

[11] Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA

[12] Univ Calif San Diego, Ctr Multimodal Imaging & Genet, La Jolla, CA 92093 USA

[13] Karolinska Inst, Dept Neurol, Clin Neurosci, Stockholm, Sweden

[14] Univ Tubingen, Ctr Genet Epidemiol, Inst Clin Epidemiol & Appl Biometry, Tubingen, Germany

[15] Cardiff Univ, MRC Ctr Neuropsychiat Genet & Genom, Cardiff, Wales

来源：

BIOLOGICAL PSYCHIATRY | 2021年 / 89卷 / 03期

基金：

美国国家卫生研究院; 英国医学研究理事会;

关键词：

SUSCEPTIBILITY LOCI; MYOCLONUS-DYSTONIA; METAANALYSIS; PLEIOTROPY; OVERLAP; PHARMACOLOGY; PHENOTYPE; CHANNELS; INSIGHTS; VARIANTS;

D O I：

10.1016/j.biopsych.2020.01.026

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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.

引用

页码：227 / 235

页数：9

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