SHARED GENETIC RISK FOR INTERNALIZING AND EXTERNALIZING DISORDERS IN MEXICAN ADOLESCENTS: THE MODERATING EFFECT OF ADVERSITY

IF 6.7 2区医学 Q1 CLINICAL NEUROLOGY

European Neuropsychopharmacology Pub Date : 2025-10-01 DOI:10.1016/j.euroneuro.2025.08.474

Gabriela Martinez-Levy , Zuriel Ceja , Jackson Thorp , Jill A. Rabinowits , I-Tzu Hung , Nathaniel Thomas , Miguel E. Rentería , Carlos Cruz Fuentes , Corina Benjet

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引用次数: 0

Abstract

Internalizing (INT) and externalizing (EXT) disorders are heritable conditions that frequently co-occur. Large-scale genome-wide association studies (GWAS) have enhanced our understanding of the polygenic architecture of these disorders; yet genetic factors associated with their comorbidity remain unclear. Here, we leverage large-scale GWAS summary statistics on INT and EXT (Thorp et al., 2021; Karlsson Linnér et al., 2021) to examine the association of shared and unique genetic liability for INT and EXT disorders in relation to phenotypic comorbidity, and explored whether childhood adversity, a well-established risk factor for these disorders moderated these associations. Participants were Mexican adolescents (n=1,134 evaluated within the framework of an epidemiological study with the Composite International Diagnostic Interview. Genomic structural equation modeling (gSEM) was used to identify common vs. unique variance associated with INT, EXT, and comorbidity of these traits. Polygenic risk scores (PGS) were subsequently created based on these results. Model fit indices supported a bifactor gSEM model (AIC = 750.978, CFI = 0.973, SRMR = 0.052) comprised of a General Psychopathology (GP) factor influencing all traits and orthogonal specific factors for externalizing and internalizing traits. The GP-PGS was significantly associated with EXT (OR = 1.3, p < 0.001) and comorbid INT-EXT (OR = 1.42, p < 0.000) outcomes. Adversities, such as parental psychopathology and neglect/abuse were associated with greater risk for all psychiatric outcomes (p < 0.001), while Parental Loss (p < 0.001) was specifically associated with EXT disorders (p < 0.000). A significant interaction was identified between GP-PGS and Loss adversity in predicting INT disorders (OR = 1.63, p < 0.016), such that the experience of loss adversity was more influential for participants with higher levels of GP genetic liability. Our results indicate the predictive utility of trans-diagnostic, genetically informed models and the importance of considering specific adversities in understanding psychiatric risk for INT and EXT comorbidity.

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墨西哥青少年内化和外化障碍的共同遗传风险：逆境的调节作用

内化（INT）和外化（EXT）障碍是经常同时发生的遗传性疾病。大规模全基因组关联研究（GWAS）增强了我们对这些疾病的多基因结构的理解；然而，与他们的合并症相关的遗传因素仍不清楚。在这里，我们利用大规模GWAS对INT和EXT的汇总统计数据（Thorp等人，2021;Karlsson linn等人，2021）来检查INT和EXT疾病的共同和独特遗传责任与表型共病的关系，并探讨童年逆境（这些疾病的一个公认的危险因素）是否会调节这些关联。参与者为墨西哥青少年（n= 1134），在一项流行病学研究框架内通过综合国际诊断访谈进行评估。基因组结构方程模型（gSEM）用于识别与INT、EXT和这些性状的共病相关的共同与独特变异。随后基于这些结果创建了多基因风险评分（PGS）。模型拟合指标支持由影响所有性状的一般精神病理学（GP）因子和影响外化性状和内化性状的正交特异因子组成的双因子gSEM模型（AIC = 750.978,CFI = 0.973,SRMR = 0.052）。GP-PGS与EXT （OR = 1.3,p < 0.001）和合并症INT-EXT （OR = 1.42,p < 0.000）结局显著相关。逆境，如父母精神病理和忽视/虐待与所有精神结局的更高风险相关（p < 0.001），而父母失去（p < 0.001）与EXT障碍特别相关（p < 0.000）。GP- pgs和损失逆境之间在预测INT障碍方面存在显著的相互作用（OR = 1.63,p < 0.016），因此损失逆境的经历对GP遗传倾向水平较高的参与者更有影响。我们的研究结果表明了跨诊断、遗传信息模型的预测效用，以及在理解INT和EXT合并症的精神风险时考虑特定逆境的重要性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

European Neuropsychopharmacology 医学-精神病学

CiteScore

10.30

自引率

5.40%

发文量

730

审稿时长

41 days

期刊介绍： European Neuropsychopharmacology is the official publication of the European College of Neuropsychopharmacology (ECNP). In accordance with the mission of the College, the journal focuses on clinical and basic science contributions that advance our understanding of brain function and human behaviour and enable translation into improved treatments and enhanced public health impact in psychiatry. Recent years have been characterized by exciting advances in basic knowledge and available experimental techniques in neuroscience and genomics. However, clinical translation of these findings has not been as rapid. The journal aims to narrow this gap by promoting findings that are expected to have a major impact on both our understanding of the biological bases of mental disorders and the development and improvement of treatments, ideally paving the way for prevention and recovery.