Genome-wide association analysis of Parkinson’s disease and schizophrenia reveals shared genetic architecture and identifies novel risk loci,Biological Psychiatry

当前位置： X-MOL 学术 › Biol. Psychiatry › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Genome-wide association analysis of Parkinson’s disease and schizophrenia reveals shared genetic architecture and identifies novel risk loci
Biological Psychiatry ( IF 10.6 ) Pub Date : 2021-02-01 , DOI: 10.1016/j.biopsych.2020.01.026
Olav B Smeland ₁ , Alexey Shadrin ₁ , Shahram Bahrami ₁ , Iris Broce ₂ , Martin Tesli ₃ , Oleksandr Frei ₁ , Katrine V Wirgenes ₄ , Kevin S O'Connell ₁ , Florian Krull ₁ , Francesco Bettella ₁ , Nils Eiel Steen ₁ , Leo Sugrue ₂ , Yunpeng Wang ₅ , Per Svenningsson ₆ , Manu Sharma ₇ , Lasse Pihlstrøm ₈ , Mathias Toft ₈ , Michael O'Donovan ₉ , Srdjan Djurovic ₁₀ , Rahul Desikan ₂ , Anders M Dale ₁₁ , Ole A Andreassen ₁

Affiliation

NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California.
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.
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
Centre for Lifespan Changes in Brain and Cognition, Department of Psychology, University of Oslo, Oslo, Norway.
Clinical Neuroscience, Department of Neurology, Karolinska Institute, Stockholm, Sweden.
Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tubingen, Tubingen, Germany.
Department of Neurology, Oslo University Hospital, Oslo, Norway.
MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom.
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway; NORMENT, Department of Clinical Science, University of Bergen, Bergen, Norway.
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.

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.

中文翻译：

帕金森病和精神分裂症的全基因组关联分析揭示了共同的遗传结构并确定了新的风险位点

背景技术帕金森病(PD) 和精神分裂症(SCZ) 是涉及多巴胺能系统失调的遗传性脑部疾病。流行病学研究报告了这些疾病之间的潜在合并症，并且运动障碍在接受抗精神病药物治疗前的 SCZ 患者中很常见。尽管如此，人们对这些疾病之间的共同遗传病因知之甚少。方基因发现。我们使用各种生物资源，对已识别的基因组位点进行功能表征。结果我们观察到 PD 的遗传富集取决于与 SCZ 的关联，反之亦然，表明多基因重叠。然后，我们使用条件 FDR 分析利用这种跨性状富集，并在条件 FDR < .01 时确定了 9 个新的 PD 风险基因座和 1 个新的 SCZ 基因座。此外，我们在联合 FDR < .05 时确定了 9 个与 PD 和 SCZ 联合相关的基因组位点。共有基因座之间的拮抗作用和激动作用方向均匀分布，这与疾病之间不显着的遗传相关性一致。在映射到共享基因座的 67 个基因中，有 65 个在人脑中表达并显示细胞类型特异性表达谱。结论总而言之，该研究增加了对 SCZ 和 PD 的遗传结构的理解，

更新日期：2021-02-01

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南

全部期刊列表>>