Brainstorming diseases Consistent classification of neuropsychiatric diseases is problematic because it can lead to misunderstanding of etiology. The Brainstorm Consortium examined multiple genome-wide association studies drawn from more than 200,000 patients for 25 brain-associated disorders and 17 phenotypes. Broadly, it appears that psychiatric and neurologic disorders share relatively little common genetic risk. However, different and independent pathways can result in similar clinical manifestations (e.g., psychosis, which occurs in both schizophrenia and Alzheimer's disease). Schizophrenia correlated with many psychiatric disorders, whereas the immunopathological affliction Crohn's disease did not, and posttraumatic stress syndrome was also largely independent of underlying traits. Essentially, the earlier the onset of a disorder, the more inheritable it appeared to be. Science, this issue p. eaap8757 Heritability analysis demonstrates how genetic variation overlaps across psychiatric disorders and behavioral traits. INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities’ assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer’s disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important “scaffolding” to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders. Subsection of genetic risk correlations among brain disorders and quantitative phenotypes. Heritability analysis of brain disorders points to pervasive sharing of genetic risk among psychiatric disorders. These correlations are largely absent among neurological disorders but are present for both groups in relation to neurocognitive quantitative phenotypes. Only significant correlations shown. Line color and solidity indicate direction and magnitude of correlation, respectively. Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

中文翻译：

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脑部常见疾病的共同遗传力分析

脑力激荡疾病 神经精神疾病的一致分类是有问题的，因为它可能导致对病因的误解。Brainstorm Consortium 检查了来自 200,000 多名患者的多项全基因组关联研究，以了解 25 种大脑相关疾病和 17 种表型。从广义上讲，精神疾病和神经系统疾病似乎具有相对较少的共同遗传风险。然而，不同且独立的途径可导致相似的临床表现（例如，精神分裂症和阿尔茨海默氏病均会出现精神病）。精神分裂症与许多精神疾病相关，而免疫病理学疾病克罗恩病则没有，创伤后应激综合征在很大程度上也与潜在特征无关。本质上，疾病发作越早，它似乎越容易继承。科学，这个问题 p。eaap8757 遗传力分析展示了遗传变异如何在精神疾病和行为特征之间重叠。引言 脑部疾病可能表现出共同的症状和大量的流行病学合并症，引发了关于其病因学重叠的争论。然而，对具有不同发病年龄、严重程度和表现的表型进行详细研究提出了相当大的挑战。最近开发的遗传力方法使我们能够准确测量来自不同个体库的两种表型之间的全基因组常见变异风险的相关性，并评估它们在基因组水平上的联系程度，或者至少是它们的遗传风险。我们使用了 265,218 名患者和 784,643 名对照参与者的全基因组关联数据，以及来自总共 1,191,588 个人的 17 种表型，以量化 25 种常见脑部疾病的遗传风险因素的重叠程度。基本原理 在过去的一个世纪里，脑部疾病的分类已经演变为反映医学和科学界对行为改变、运动功能丧失或意识改变等临床现象的假定根本原因的评估。可直接观察到的现象（例如栓塞、蛋白质缠结或异常电活动模式的存在）通常定义神经系统疾病并将其与精神疾病区分开来。了解脑部疾病和相关表型的遗传基础和分类区别可能会为寻找其生物学机制提供信息。结果表明，精神疾病的常见变异风险显着相关，尤其是在注意力缺陷多动障碍 (ADHD)、双相情感障碍、重度抑郁症 (MDD) 和精神分裂症之间。相比之下，神经系统疾病之间以及与精神疾病之间的区别似乎更大，但偏头痛除外，它与 ADHD、MDD 和图雷特综合征显着相关。我们证明，在一般人群中，人格特质神经质与几乎所有精神疾病和偏头痛都显着相关。我们还确定了一般人群中疾病与早年认知测量（例如，受教育年限和大学学历）之间存在显着的遗传共享，证明与几种精神疾病（例如，神经性厌食症和双相情感障碍）以及与几种神经表型（例如，阿尔茨海默氏病和缺血性中风）呈负相关，尽管后者被认为是由生命后期发生的特定过程引起的。还进行了广泛的模拟以了解统计功效、诊断错误分类和表型异质性如何影响遗传相关性。结论 许多精神疾病之间的高度遗传相关性进一步证明，它们目前的临床界限并没有反映出不同的潜在致病过程，至少在遗传水平上是这样。与神经系统疾病相比，这表明精神疾病具有深刻的相互关联性，并强调需要改进精神疾病诊断。遗传信息分析可能提供重要的“脚手架”来支持这种精神病学分类学的重组，这可能需要整合多层次的信息。相比之下，我们发现有限的证据表明神经系统疾病之间或神经系统疾病和精神疾病之间存在广泛的共同遗传风险共享。我们表明，精神疾病和神经系统疾病都与认知和人格测量具有很强的相关性。需要进一步研究来评估重叠遗传对精神病理学的贡献是否会影响治疗选择。最终，这些发展可能为减少异质性和改进精神疾病的诊断和治疗铺平道路。脑部疾病和定量表型之间的遗传风险相关性的子部分。脑部疾病的遗传力分析表明，精神疾病之间普遍存在遗传风险。这些相关性在神经系统疾病中基本上不存在，但与神经认知定量表型相关的两组都存在。仅显示显着相关性。线条颜色和实心度分别表示相关的方向和大小。脑部疾病可以表现出相当大的流行病学合并症，并且经常有共同的症状，这引发了关于它们病因学重叠的争论。我们量化了 265,218 名患者和 784,643 名对照参与者的全基因组关联研究中 25 种脑部疾病的遗传共享，并评估了它们与来自 1,191,588 名个体的 17 种表型的关系。精神疾病具有共同的变异风险，而神经系统疾病似乎彼此之间以及与精神疾病之间的区别更大。我们还确定了疾病和许多大脑表型之间的显着共享，包括认知测量。此外，我们进行了模拟以探索统计功效、诊断错误分类和表型异质性如何影响遗传相关性。这些结果强调了常见遗传变异作为脑部疾病危险因素的重要性，以及基于遗传力的方法在理解其病因学方面的价值。和表型异质性影响遗传相关性。这些结果强调了常见遗传变异作为脑部疾病危险因素的重要性，以及基于遗传力的方法在理解其病因学方面的价值。和表型异质性影响遗传相关性。这些结果强调了常见遗传变异作为脑部疾病危险因素的重要性，以及基于遗传力的方法在理解其病因学方面的价值。