[...] Exploring the genetic background of depressive symptoms in the absence of recent stress exposure using a GWAS approach, 2025, Erdelyi-Hamza+

[forestglip]

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

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

Highlights
• Heterogeneity of depression in study often obscures significant genetic findings.
• Depression developing independently of stress exposure is a distinct subtype.
• DCC gene was significantly associated with stress-free depression.
• Tissue specific upregulation was identified in brain areas relevant to depression.
• Our findings may help separate depression subtypes on a genetic level.

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.

Link (Journal of Affective Disorders) [Paywall]

 

[Utsikt]

I wonder how they defined «depressive symptoms»?

 

[rvallee]

I wonder even more how they define "stressful life events", because whew is that open to not just some, but all the interpretation.

Because we've seen so many studies where the bar for "stressful life events" is so low that they basically happen every day. Which makes all of this entirely pointless, especially as what some people find bad stress, others find its absence boring. This is impossible to research in the way they are doing it. The way depression is defined, it's 100x more vague and heterogeneous than any of the discriminated chronic illnesses.

Plus when you notice that this gets published in the Journal of affective disorders, it gets even more silly as how can 'depression', however it's loosely defined, be affective/caused by stress (usually what it means) if it's independent of stress?

Honestly, comparative medieval poetry is a more rigorous discipline than this, and it's basically 0.001 rigors, which is a unit I made up but is quite funny when you think about it.

Actually, this reminds me of an article I saw a few days ago, I should look for it, out of Sweden, I think, that was about how burnout, which is usually defined as some form of overwork, is mostly independent of work, since only a small % with burnout, which is a vague category in which ME/CFS is loosely included, attribute work as the cause. So it's overwork without work being significant. Which makes as much sense as deconditioning without deconditioning, but this one has been going strong literally for decades so clearly this is not a discipline that is bothered by the equivalent of a pasta plate with no pasta still being called a pasta plate.

Or, put another way: words and their meaning, why bother?

(Ah, here's the article, I'll post the study in another thread: https://www.sciencealert.com/burnout-might-not-actually-be-a-work-problem-after-all-study-shows).

 

[Kiristar]

From the abstract It looks like they allowed respondents to decide if they'd had a stressful event in the last two years or not.

Stress is subjective so any attempt to standardise would be doomed to failure. One person might find a parental bereavement incredibly stressful another with a distant relationship might not.

I actually find the idea of understanding the genetics of depression very interesting given it's frequent conflating with ME.

That initial eligibility criteria aside, I wonder how well the rest of the study holds up to S4MEs methodological scrutiny?