The Australian Genetics of Depression Study: New Risk Loci and Dissecting Heterogeneity Between Subtypes,Biological Psychiatry

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The Australian Genetics of Depression Study: New Risk Loci and Dissecting Heterogeneity Between Subtypes
Biological Psychiatry ( IF 9.6 ) Pub Date : 2021-11-02 , DOI: 10.1016/j.biopsych.2021.10.021
Brittany L Mitchell ₁ , Adrian I Campos ₂ , David C Whiteman ₃ , Catherine M Olsen ₃ , Scott D Gordon ₃ , Adam J Walker ₄ , Olivia M Dean ₅ , Michael Berk ₆ , Ian B Hickie ₇ , Sarah E Medland ₃ , Naomi R Wray ₈ , Nicholas G Martin ₃ , Enda M Byrne ₉

Affiliation

QIMR Berghofer Medical Research Institute, Brisbane, Australia; School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Australia.
QIMR Berghofer Medical Research Institute, Brisbane, Australia; School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, Australia; Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, Australia.
Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, Australia; Florey Institute for Neuroscience and Mental Health and the Department of Psychiatry, The University of Melbourne, Melbourne, Australia.
Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, Australia; Florey Institute for Neuroscience and Mental Health and the Department of Psychiatry, The University of Melbourne, Melbourne, Australia; Orygen, The National Centre of Excellence in Youth Mental Health, Centre for Youth Mental Health, Australia.
Brain and Mind Centre, The University of Sydney, Sydney, New South Wales, Australia.
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia; Queensland Brain Institute, The University of Queensland, Brisbane, Australia.
Child Health Research Centre, The University of Queensland, Brisbane, Australia; Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.

Background

Major depressive disorder (MDD) is a common and highly heterogeneous psychiatric disorder, but little is known about the genetic characterization of this heterogeneity. Understanding the genetic etiology of MDD can be challenging because large sample sizes are needed for gene discovery—often achieved with a trade-off in the depth of phenotyping.

Methods

The Australian Genetics of Depression Study is the largest stand-alone depression cohort with both genetic data and in-depth phenotyping and comprises a total of 15,792 participants of European ancestry, 92% of whom met diagnostic criteria for MDD. We leveraged the unique nature of this cohort to conduct a meta-analysis with the largest publicly available depression genome-wide association study to date and subsequently used polygenic scores to investigate genetic heterogeneity across various clinical subtypes of MDD.

Results

We increased the number of known genome-wide significant variants associated with depression from 103 to 126 and found evidence of association of novel genes implicated in neuronal development. We found that a polygenic score for depression explained 5.7% of variance in MDD liability in our sample. Finally, we found strong support for genetic heterogeneity in depression with differential associations of multiple psychiatric and comorbid traits with age of onset, longitudinal course, and various subtypes of MDD.

Conclusions

Until now, this degree of detailed phenotyping in such a large sample of MDD cases has not been possible. Along with the discovery of novel loci, we provide support for differential pathways to illness models that recognize the overlap with other common psychiatric disorders as well as pathophysiological differences.

中文翻译：

澳大利亚抑郁症遗传学研究：新的风险位点和剖析亚型之间的异质性

背景

重度抑郁症 (MDD) 是一种常见且高度异质性的精神疾病，但对这种异质性的遗传特征知之甚少。了解 MDD 的遗传病因可能具有挑战性，因为基因发现需要大量样本——通常需要权衡表型分析的深度。

方法

澳大利亚抑郁症遗传学研究是最大的独立抑郁症队列，具有遗传数据和深入的表型分析，共有 15,792 名欧洲血统的参与者，其中 92% 符合 MDD 的诊断标准。我们利用该队列的独特性对迄今为止最大的公开可用的抑郁症全基因组关联研究进行荟萃分析，随后使用多基因评分来研究 MDD 各种临床亚型的遗传异质性。

结果

我们将与抑郁症相关的已知全基因组显着变异的数量从 103 个增加到 126 个，并发现了与神经元发育有关的新基因相关的证据。我们发现抑郁症的多基因评分解释了我们样本中 5.7% 的 MDD 责任差异。最后，我们发现抑郁症的遗传异质性与多种精神和共病特征与发病年龄、纵向病程和 MDD 的各种亚型之间存在差异关联。