目的 明确注意缺陷多动障碍(ADHD)与多种情绪状态的因果关系及神经解剖学机制,评估前额叶皮层体积的中介作用,为 ADHD 早期干预提供理论支撑。方法 基于2018—2023年公开全基因组关联研究(GWAS)数据,采用双样本双向孟德尔随机化(MR)及中介MR分析,纳入12种情绪状态(GWAS样本量n=380 506)、ADHD(n=225 534)及前额叶皮层体积(n=32 418)的遗传数据,通过逆方差加权(IVW)法、多变量MR+Delta法量化效应,结合多重稳健性检验及年龄分层(儿童6~12岁、青少年13~19岁、成人≥20岁)分析。结果 内疚(OR=2.64,95%CI:1.42~4.91,P=0.002)和厌倦(OR=2.18,95%CI:1.48~3.20,P<0.001)与ADHD呈显著正向因果关联,无反向因果效应;前额叶皮层体积在二者关联中起中介作用,中介比例分别为74.4%和68.3%(P<0.001),且青少年亚组中介效应最强,中介比例分别为83.7%、77.8%(P<0.001)。结论 内疚、厌倦情绪是 ADHD 的潜在上游风险因素,前额叶皮层体积介导二者关联,青少年期为关键敏感阶段。本研究基于欧洲人群遗传数据开展,结论的人群适用性仍需结合不同遗传背景进一步验证,但仍为 ADHD 早期干预提供潜在新靶点。
Abstract
Objective To clarify the causal relationship and neuroanatomical mechanisms between attention-deficit/hyperactivity disorder (ADHD) and various emotional states, and to evaluate the mediating role of prefrontal cortex volume, so as to provide a theoretical basis for early intervention in ADHD. Methods Based on publicly available Genome-Wide Association Study (GWAS) data from 2018 to 2023, two-sample bidirectional Mendelian Randomization (MR) and mediation MR analysis were adopted.The study incorporated genetic data for 12 emotional traits (n=380 506), ADHD (n=225 534), and prefrontal cortex volume (n=32 418).Effects were quantified using the Inverse Variance Weighted (IVW) method and multivariate MR+Delta method, combined with multiple robustness tests and stratified analysis by age (children: 6 - 12 years old, adolescents: 13 - 19 years old, adults: ≥20 years old). Results Guilt (OR=2.64, 95% CI: 1.42 - 4.91, P=0.002) and boredom (OR=2.18, 95% CI: 1.48 - 3.20, P<0.001) exhibited significant positive causal associations with ADHD, with no evidence of reverse causality.Prefrontal cortex volume played a major mediating role in these associations, accounting for 74.4% and 68.3% of the total effect, respectively (P<0.001).Age-stratified analysis indicated that this mediating effect was strongest during adolescence (13 - 19 years), with mediation proportions reaching 83.7% and 77.8% (P<0.001). Conclusions Guilt and boredom are potential upstream risk factors for ADHD, and prefrontal cortex volume mediates the association between these two emotions and ADHD.Although this study is based on genetic data from European populations and its generalizability to diverse genetic backgrounds requires further verification, it identifies potential new targets for early intervention in ADHD.
关键词
情绪 /
注意缺陷多动障碍 /
厌倦 /
内疚 /
前额叶皮层
Key words
emotion /
attention-deficit/hyperactivity disorder /
boredom /
guilt /
prefrontal cortex
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参考文献
[1] Epstein JN, Loren RE.Changes in the definition of ADHD in DSM-5: Subtle but important[J].Neuropsychiatry (Lond), 2013, 3(5): 455-458.
[2] 孙向红,陈雪峰,陈雪峰,等.心理健康蓝皮书:中国国民心理健康发展报告 (2023-2024)[M].北京:社会科学文献出版社,2024.
Sun XH, Chen XF, Chen XF,et al.Mental health blue book: Report on national mental health development in China (2023-2024)[M].Beijing: Social Sciences Academic Press (China), 2024.(in Chinese)
[3] 李思迅, 王美雯, 杨燕平, 等. 情绪调节与注意缺陷多动障碍患儿焦虑/抑郁症状:社交问题的中介效应和家庭功能的调节[J]. 四川大学学报(医学版), 2024, 55(2): 346-352.
Liu SX, Wang MW, Yang YP, et al.Effect of emotion regulation on anxiety/depression symptoms in children with attention-deficit/hyperactivity disorder: The mediating role of social problems and the moderating role of family functioning[J].Joumal of Sichuan University(Medical Science Edition),2024, 55(2): 346-352.(in Chinese)
[4] Richmond RC, Davey Smith G.Mendelian randomization: Concepts and scope[J].Cold Spring Harb PerspectMed, 2022, 12(1):a040501.
[5] Shaw P, Stringaris A, Nigg J, et al.Emotion dysregulation in attention deficit hyperactivity disorder[J].Am J Psychiatry, 2014, 171(3): 276-293.
[6] Nagel M, Watanabe K, Stringer S, et al.Item-level analyses reveal genetic heterogeneity in neuroticism[J].Nat Commun, 2018, 9(1): 905.
[7] Demontis D, Walters GB, Athanasiadis G, et al.Author correction: Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains[J].Nat Genet, 2023, 55(4): 730.
[8] Skrivankova VW, Richmond RC, Woolf BAR, et al.Strengthen-ing the reporting of observational studies in epidemiology using mendelian randomisation (STROBE-MR): Explanation and elaboration[J].BMJ, 2021, 375: n2233.
[9] Lawlor DA, Harbord RM, Sterne JA, et al.Mendelian randomization: Using genes as instruments for making causal inferences in epidemiology[J].Stat Med, 2008, 27(8): 1133-1163.
[10] Grasby KL, Jahanshad N, Painter JN, et al.The genetic architecture of the human cerebral cortex[J].Science, 2020, 367(6484).
[11] Bowden J, Davey Smith G, Burgess S.Mendelian randomization with invalid instruments: Effect estimation and bias detection through Egger regression[J].Int J Epidemiol, 2015, 44(2): 512-525.
[12] Verbanck M, Chen CY, Neale B, et al.Publisher correction: Detection of widespread horizontal pleiotropy in causal relationships inferred from mendelian randomization between complex traits and diseases[J].Nat Genet, 2018, 50(8): 1196.
[13] Mojzisch A, Schulz-Hardt S.Being fed up: A social cognitive neuroscience approach to mental satiation[J].Ann N Y Acad Sci, 2007, 1118: 186-205.
[14] Tong J, Li N, Hu F, et al.Metabolic improvement mediates the causal relationship between GLP-1 receptor agonists and myocardial infarction: A mendelian randomization and mediation analysis study[J].Diabetes Care, 2026,49(1):171-178.
[15] Shen J, Tozer DJ, Markus HS, et al.Network efficiency mediates the relationship between vascular burden and cognitive impairment: A diffusion tensor imaging study in UK biobank[J].Stroke, 2020, 51(6): 1682-1689.
[16] Newark PE, Elsasser M, Stieglitz RD.Self-esteem, self-efficacy, and resources in adults with ADHD[J].J Atten Disord, 2016, 20(3): 279-290.
[17] Akse J, Hale WW, Engels RC, et al.Stability and change in personality type membership and anxiety in adolescence[J].J Adolesc, 2007, 30(5): 813-834.
[18] Caye A, Spadini AV, Karam RG, et al.Predictors of persistence of ADHD into adulthood: A systematic review of the literature and meta-analysis[J].Eur Child Adolesc Psychiatry, 2016, 25(11): 1151-1159.
[19] Deng J.Cultural influences on emotional display rules[D].London: Brunel University,2019.
[20] Bramham J, Young S, Bickerdike A, et al.Evaluation of group cognitive behavioral therapy for adults with ADHD[J].J Atten Disord, 2009, 12(5): 434-441.
[21] Song J, Fogarty K, Suk R, et al.Behavioral and mental health problems in adolescents with ADHD: Exploring the role of family resilience[J].J Affect Disord, 2021, 294: 450-458.
基金
山东省自然科学基金(ZR2021MH296); 山东省医药卫生科技项目(202412030598); 山东省中医药科技项目(Z20243204)
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