Polygenic predisposition to transdiagnostic symptom dimensions and treatment outcomes across psychiatric disorders

IF 3.9 2区医学 Q1 CLINICAL NEUROLOGY

Progress in Neuro-Psychopharmacology & Biological Psychiatry Pub Date : 2025-10-02 DOI:10.1016/j.pnpbp.2025.111512

Paolo Abondio , Giuseppe Fanelli , Valentina Baldini , Maria Giulia Bacalini , Siegfried Kasper , Joseph Zohar , Daniel Souery , Stuart Montgomery , Diego Albani , Gianluigi Forloni , Panagiotis Ferentinos , Dan Rujescu , Julien Mendlewicz , Alessandro Serretti , Alessio Maria Monteleone , Luigi Grassi , MNESYS - Mood and Psychosis Sub-ProjecEt (Spoke 5) , Anna Rita Atti , Marco Menchetti , Chiara Fabbri , Diana De Ronchi

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Abstract

Background

Mood and psychotic disorders, including major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ), show overlapping symptoms that challenge diagnostic boundaries and may inform personalised treatments. We examined the contribution of genetic liability to transdiagnostic symptom dimensions in treatment outcomes across disorders using polygenic scores (PGSs).

Methods

We analysed two MDD cohorts (total N = 2548), one BD cohort (N = 755), and one SCZ cohort (N = 449). Outcomes included treatment resistance, symptomatic remission, and change in functioning defined using cohort-specific data. PGSs for anhedonia, anxiety, sociability, resilience, cognitive and sleep-related traits were computed using SBayesRC. Regressions adjusted for potential confounders were run in each cohort and results meta-analysed with random-effects models; heterogeneity was assessed with leave-one-out and influence diagnostics, and meta-regressions. Multiple testing was controlled using a Bonferroni correction adjusted for the effective number of independent tests (α_adj = 0.0034).

Results

In meta-analyses, no result survived multiple testing correction. The strongest signal was for the Trail Making Test Part B PGS, indexing worse executive function/processing speed, and non-remission (OR = 1.13, p = 0.012; I² = 13 %); modelling diagnosis (mood disorders vs SCZ) reduced heterogeneity to I² = 0 %, and leave-one-out excluding SCZ reached statistical significance (OR = 1.17, p = 0.001). Verbal-numerical reasoning PGS, indexing predisposition to higher fluid intelligence, was nominally associated with improved functioning (β = −0.06, p = 0.016), confirmed in leave-one-out excluding BD (β = −0.07, p = 0.0095).

Conclusion

PGSs for cognitive traits showed trait- and diagnosis-specific associations with treatment outcomes. Cross-diagnostic analyses may identify shared genetic influences, but variability in symptom expression across disorders may introduce heterogeneity and reduce the detectability of such effects.

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多基因易感性对跨精神疾病的跨诊断症状维度和治疗结果的影响。

背景：情绪和精神障碍，包括重度抑郁症（MDD）、双相情感障碍（BD）和精神分裂症（SCZ），表现出重叠的症状，挑战诊断界限，可能需要个性化治疗。我们使用多基因评分（PGS）检查了遗传倾向性对跨疾病治疗结果中跨诊断症状维度的贡献。方法：我们分析了两个MDD队列（总N = 2548），一个BD队列（N = 755）和一个SCZ队列（N = 449）。结果包括治疗抵抗、症状缓解和使用特定队列数据定义的功能改变。使用SBayesRC计算快感缺乏、焦虑、社交、恢复力、认知和睡眠相关特征的pgs。对每个队列进行校正潜在混杂因素的回归分析，并用随机效应模型对结果进行meta分析；异质性通过遗漏诊断和影响诊断以及元回归进行评估。多重检验采用Bonferroni校正控制，校正独立检验的有效数量（αadj = 0.0034）。结果：在荟萃分析中，没有结果通过多次检验校正。最强烈的信号是线索制作测试B部分PGS，指标执行功能/处理速度变差，无缓解（OR = 1.13,p = 0.012;I2 = 13 %）；建模诊断（情绪障碍vs SCZ）将异质性降低到I2 = 0 %，排除SCZ的左一排除达到统计学意义（OR = 1.17,p = 0.001）。语言-数值推理能力PGS，显示更高流体智力的倾向，在名义上与功能改善有关（β = -0.06,p = 0.016），在排除BD的左一组中得到证实（β = -0.07,p = 0.0095）。结论：认知特征的pgs与治疗结果具有特质和诊断特异性的相关性。交叉诊断分析可以确定共同的遗传影响，但不同疾病之间症状表达的可变性可能会引入异质性，并降低这种影响的可检测性。

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

Progress in Neuro-Psychopharmacology & Biological Psychiatry 医学-精神病学

CiteScore

12.00

自引率

1.80%

发文量

153

审稿时长

56 days

期刊介绍： Progress in Neuro-Psychopharmacology & Biological Psychiatry is an international and multidisciplinary journal which aims to ensure the rapid publication of authoritative reviews and research papers dealing with experimental and clinical aspects of neuro-psychopharmacology and biological psychiatry. Issues of the journal are regularly devoted wholly in or in part to a topical subject. Progress in Neuro-Psychopharmacology & Biological Psychiatry does not publish work on the actions of biological extracts unless the pharmacological active molecular substrate and/or specific receptor binding properties of the extract compounds are elucidated.