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

Erdélyi-Hamza, Berta and Török, Dóra and Krause, Sándor and Eszlári, Nóra and Bagdy, György and Juhász, Gabriella and Gonda, Xénia (2025) Disentangling nature and nurture: Exploring the genetic background of depressive symptoms in the absence of recent stress exposure using a GWAS approach. JOURNAL OF AFFECTIVE DISORDERS, 388. No. 119731. ISSN 0165-0327

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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.

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