Disentangling nature and nurture: Exploring the genetic background of depressive symptoms in the absence of recent stress exposure using a GWAS approach

IF 4.9 2区医学 Q1 CLINICAL NEUROLOGY

Journal of affective disorders Pub Date : 2025-06-18 DOI:10.1016/j.jad.2025.119731

Berta Erdelyi-Hamza , Dora Torok , Sandor Krause , Nora Eszlari , Gyorgy Bagdy , Gabriella Juhasz , Xenia Gonda

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引用次数: 0

Abstract

Background

Depression triggered by stress exposure versus depression appearing independently of it are two distinct subtypes. Analyzing their genetic background separately may bring us closer to decreasing the noise stemming from heterogeneity. We focused on the genetic background of depressive symptoms appearing in the absence of recent stress exposure with a genome-wide analysis approach and to reveal biological connections between genetic background, brain functioning, and tissue specific differences.

Methods

We included nearly 200,000 subjects reporting no stressful life events in the past two years with data on current depressive symptom severity. Following genotyping and quality control, 6,076,829 genetic variants were analyzed. GWAS results were evaluated on SNP, gene, and gene-set levels.

Results

64 SNPs with suggestive significance were identified, one SNP (rs60939828 p = 5.92 × 10⁻¹¹), located in DCC survived Bonferroni correction. DCC (p = 4.16 × 10⁻¹⁰) was also among three genes significant in gene-level associations. We identified tissue-specific upregulation in relevant brain areas where the more significantly a gene was associated with depressive symptoms, the higher it was expressed in brain areas including the cerebellar hemisphere (p = 4.0131 × 10⁻⁵), cerebellum (p = 1.79 × 10⁻⁵), frontal cortex (p = 2.9 × 10⁻⁴), cortex (p = 3.4 × 10⁻⁴), and anterior cingulate cortex (p = 9 × 10⁻⁴). Heritability estimation analysis revealed a 7.3 % heritability.

Conclusion

Our findings contribute to separating subtypes of depression on a genetic level. Future studies need to compare our results to findings in depression developing following exposure to severe stress to see what genetic markers and implicated pathways may separate these fundamentally distinct subtypes of depressive symptoms, paving the way for precision guidelines for diagnosing and treating depression.

Abstract Image

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解开先天和后天的纠缠：使用GWAS方法在没有近期压力暴露的情况下探索抑郁症状的遗传背景。

背景：由压力引发的抑郁症和独立于压力而出现的抑郁症是两种不同的亚型。分别分析它们的遗传背景可以使我们更接近于减少异质性产生的噪音。我们通过全基因组分析方法关注在没有近期压力暴露的情况下出现抑郁症状的遗传背景，并揭示遗传背景、脑功能和组织特异性差异之间的生物学联系。方法：我们纳入了近20万名报告过去两年中没有压力生活事件的受试者，并提供了当前抑郁症状严重程度的数据。通过基因分型和质量控制，分析了6076829个遗传变异。GWAS结果在SNP、基因和基因集水平上进行评估。结果：鉴定出64个具有提示意义的SNP， 1个位于DCC的SNP （rs60939828 p = 5.92 × 10-11）在Bonferroni校正中存活。DCC （p = 4.16 × 10-10）也是在基因水平上具有显著相关性的三个基因之一。我们确定的组织upregulation有关的大脑区域,更重要的是一个基因是与抑郁症状有关,高表达于大脑区域包括小脑半球(p = 4.0131 × 纯)、小脑(p = 1.79 × 纯),额叶皮质(p = 2.9 ×4 打败),皮层(p = 3.4 ×4 打败),和前扣带皮层(p = 9 ×4 打败)。遗传率估计分析显示，遗传率为7.3 %。结论：我们的发现有助于在基因水平上分离抑郁症的亚型。未来的研究需要将我们的结果与暴露于严重压力下的抑郁症的研究结果进行比较，以了解哪些遗传标记和相关途径可以区分这些根本不同的抑郁症状亚型，为诊断和治疗抑郁症的精确指导铺平道路。

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

Journal of affective disorders 医学-精神病学

CiteScore

10.90

自引率

6.10%

发文量

1319

审稿时长

9.3 weeks

期刊介绍： The Journal of Affective Disorders publishes papers concerned with affective disorders in the widest sense: depression, mania, mood spectrum, emotions and personality, anxiety and stress. It is interdisciplinary and aims to bring together different approaches for a diverse readership. Top quality papers will be accepted dealing with any aspect of affective disorders, including neuroimaging, cognitive neurosciences, genetics, molecular biology, experimental and clinical neurosciences, pharmacology, neuroimmunoendocrinology, intervention and treatment trials.