Waldman Irwin D, Poore Holly E, Luningham Justin M, Yang Jingjing
Department of Psychology, Emory University, Atlanta, GA, USA.
Department of Population Health Sciences, Georgia State University, Atlanta, GA, USA.
World Psychiatry. 2020 Oct;19(3):350-359. doi: 10.1002/wps.20772.
Genome-wide association studies (GWAS) have revealed hundreds of genetic loci associated with the vulnerability to major psychiatric disorders, and post-GWAS analyses have shown substantial genetic correlations among these disorders. This evidence supports the existence of a higher-order structure of psychopathology at both the genetic and phenotypic levels. Despite recent efforts by collaborative consortia such as the Hierarchical Taxonomy of Psychopathology (HiTOP), this structure remains unclear. In this study, we tested multiple alternative structural models of psychopathology at the genomic level, using the genetic correlations among fourteen psychiatric disorders and related psychological traits estimated from GWAS summary statistics. The best-fitting model included four correlated higher-order factors - externalizing, internalizing, thought problems, and neurodevelopmental disorders - which showed distinct patterns of genetic correlations with external validity variables and accounted for substantial genetic variance in their constituent disorders. A bifactor model including a general factor of psychopathology as well as the four specific factors fit worse than the above model. Several model modifications were tested to explore the placement of some disorders - such as bipolar disorder, obsessive-compulsive disorder, and eating disorders - within the broader psychopathology structure. The best-fitting model indicated that eating disorders and obsessive-compulsive disorder, on the one hand, and bipolar disorder and schizophrenia, on the other, load together on the same thought problems factor. These findings provide support for several of the HiTOP higher-order dimensions and suggest a similar structure of psychopathology at the genomic and phenotypic levels.
全基因组关联研究（GWAS）已经揭示了数百个与主要精神疾病易感性相关的基因位点，GWAS后分析表明这些疾病之间存在显著的遗传相关性。这一证据支持了在遗传和表型水平上存在精神病理学高阶结构的观点。尽管诸如精神病理学层次分类法（HiTOP）等合作联盟最近做出了努力，但这种结构仍不明确。在本研究中，我们使用从GWAS汇总统计数据估计的14种精神疾病和相关心理特征之间的遗传相关性，在基因组水平上测试了多种精神病理学替代结构模型。最佳拟合模型包括四个相关的高阶因素——外化、内化、思维问题和神经发育障碍——它们与外部效度变量呈现出不同的遗传相关模式，并解释了其组成疾病中的大量遗传变异。一个包括精神病理学一般因素以及四个特定因素的双因素模型拟合效果比上述模型更差。我们测试了几种模型修正，以探索某些疾病——如双相情感障碍、强迫症和饮食失调症——在更广泛的精神病理学结构中的位置。最佳拟合模型表明，一方面饮食失调症和强迫症，另一方面双相情感障碍和精神分裂症，共同加载在同一个思维问题因素上。这些发现为HiTOP的几个高阶维度提供了支持，并表明在基因组和表型水平上存在相似的精神病理学结构。
