Genome-wide meta-analysis of quantitatively measured generalized anxiety symptoms in individuals of European ancestry, 2026, Skelton et al.

[SNT Gatchaman]

Genome-wide meta-analysis of quantitatively measured generalized anxiety symptoms in individuals of European ancestry

Spoiler: Authors

Skelton, Megan; Mitchell, Brittany L; Assary, Elham; Li, Danyang; Morneau-Vaillancourt, Genevieve; Murphy, Alan E; ter Kuile, Abigail R; Wang, Rujia; Adams, Mark J; Byrne, Enda M; Corfield, Elizabeth C; Grimes, Poppy Z; Hannigan, Laurie J; Hu, Jihua; Kõiv, Kadri; Kwong, Alex S F; Papiol, Sergi; Pettersen, Johanne H; Pistis, Giorgio; Castelao, Enrique; Strom, Nora I; van der Most, Peter J; Andreassen, Ole A; Erhardt-Lehmann, Angelika; Havdahl, Alexandra; Skene, Nathan; Verhulst, Brad; Weber, Heike; Armour, Chérie; Ask, Helga; Copeland, William E; Dannlowski, Udo; Deckert, Jürgen; Domschke, Katharina; Hickie, Ian B; Lehto, Kelli; Lonsdorf, Tina B; Lueken, Ulrike; Lupton, Michelle K; Medland, Sarah E; McIntosh, Andrew M; Oldehinkel, Albertine J; Preisig, Martin; Reif, Andreas; Snieder, Harold; Walters, James T R; Wray, Naomi R; Hartman, Catharina A; Martin, Nicholas G; Hettema, John M; Breen, Gerome; Coleman, Jonathan R I; Eley, Thalia C

Anxiety is heritable and exists on a continuum, with symptoms ranging from adaptive threat response to clinical disorder. Here we performed a genome-wide association meta-analysis of generalized anxiety symptom severity in 693,869 individuals of European ancestry from 14 cohorts.

We identified 80 independent genome-wide significant variants within 74 loci, 39 of which were newly associated with anxiety. SNP-based heritability was 5.9% (posterior s.d. = 0.15%). Polygenic scores were significantly associated with anxiety symptom severity and disorder in European, African and South Asian ancestry samples (R2 = 1.2–2.9%).

Significant genetic correlations (rg) were estimated with mental and physical health traits, including case–control anxiety, neuroticism and depression (rg = 0.71–0.85), irritable bowel syndrome (rg = 0.57), coronary artery disease, endometriosis and migraine (rg = 0.20–0.27). Gene-based and pathway analyses implicated synaptic and axonal processes, with enriched expression in the brain.

These findings highlight the discovery power gained from analysing a quantitative trait rather than a case–control phenotype in anxiety genetics.

Web | DOI | PDF | Nature Human Behaviour | Open Access

 

[SNT Gatchaman]

The strongest intragenic association was estimated for rs1476548 within PCLO, which was also implicated through positional mapping, eQTL mapping and gene-based association testing. PCLO encodes a protein involved in regulating presynaptic structure and neurotransmitter release. This gene has long been of interest in major depressive disorder, with recent evidence also linking it to anxiety disorders.

Another gene of interest from our analysis was SORCS3, which was supported by multiple lines of evidence in the recent PGC-ANX case–control anxiety GWAS. SORCS3 plays a role in postsynaptic functioning and glutamate receptor regulation, particularly in the hippocampus. It has been linked to memory and learning processes, specifically synaptic depression and fear extinction, and mental health and neurodevelopmental conditions, including major depressive disorder, Tourette syndrome, attention deficit hyperactivity disorder and autism.

A network medicine approach to investigating ME/CFS pathogenesis in severely ill patients: a pilot study (2025) —

We examined the nine genes with recurrent variants in the SIPS patients, specifically ACADL, BRCA1, CFTR, COX10, HABP2, MFRP, PCLO, PRKN, and ZFPM2.

SORCS3 came up in Genome-wide association study of multisite chronic pain in UK Biobank (2019)

 

[ME/CFS Science Blog]

See a couple of familiar genes from our DecodeME analysis:

DCC on chr18
VRK2 on chr2
SOX6 on chr11


The top hit here was on chromosome 1:73,847,802 (chr1:73382119 on GRCh38 coordinates). DecodeME also seems to have a signal there, which we thought might point to NEGR1.



I suspect the similarity is based on this:

Gene-based and pathway analyses implicated synaptic and axonal processes, with enriched expression in the brain

As DecodeME pointed to similar neural processes.

Suspect it might also explain why chronic pain, tiredness, and IBS show a stronger genetic correlation with anxiety than many other diseases. These might also have a stronger neuronal component (which would explain why they have also remained poorly explained).

 

[ScoutB]

I suspect the similarity is based on this:
>> Gene-based and pathway analyses implicated synaptic and axonal processes, with enriched expression in the brain
As DecodeME pointed to similar neural processes.

Relatedly, I've been reading a lot of Kevin Mitchell's blog posts (one of the authors of Conceptual and methodological flaws undermine claims of a link between the gut microbiome and autism). A point he makes a couple of times is that there's a lot of shared genetic risk for different neurologic and psychiatric illnesses. We've seen this ourselves in several GWAS, and he also says it's true even when you look at rare mutations (which you'd think would have the best chance of causing a unique specific problem).

In What have we learned from psychiatric genetics? The view from 2022, he says:

[...] the same [copy number variants] showed up in patients with diverse conditions, including schizophrenia, bipolar disorder, autism, intellectual disability, and even epilepsy. These rare mutations thus clearly increased risk for psychiatric and neurological conditions in a non-specific fashion, with some other factors required to explain what conditions actually emerged in any individual carriers. Indeed, the same [copy number variants] are often found (at lower frequency) in clinically unaffected individuals in the general population.

He writes in a couple places about what this could mean (that the genes have to do with general robustness, and/or that our diagnostic categories are groupings of many disorders), but he's also thinking about developmental disorders so I'm not sure if the logic would apply to ME/CFS. On the other hand, it's interesting we are seeing the same thing in a seemingly non-developmental disorder?

 

[SugarSquared]

It’s always so interesting when research seems to point at me and my conditions. Sometimes, it feels like there’s connections between everything, like a big spiderweb! Anxiety, IBS, autism. A neurologist will be able to tell me if I have headaches or migraines, but I have a family history of migraines. I’m on the waitlist for a pelvic MRI, but if I end up having adenomyosis, endometriosis is not far off! Fascinating stuff.

 

[ChronicallyOverIt]

Is there a gene DCC thread? On mobile and search isn’t searching…


“large and increasing number of studies show a tight link between genetic variation in the Netrin-1/DCCsystem and MDD. For a detailed description of the role of Netrin-1 and DCC receptors in stress-induced behavioral alterations in rodents”

Frontiers | Awakening the dormant: Role of axonal guidance cues in stress-induced reorganization of the adult prefrontal cortex leading to depression-like behavior

Major depressive disorder (MDD) is a chronic and disabling disorder affecting roughly 280 million people worldwide. While multiple brain areas have been impl...

www.frontiersin.org

 

[ChronicallyOverIt]

Huh DCC popped up here too:

Thread 'Neurodevelopment Genes Encoding Olduvai Domains Link Myalgic Encephalomyelitis to Neuropsychiatric Disorders, 2025, Lidbury et al'

Jun 18, 2025

Abstract:
Background/Objectives: The aetiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a chronic and severe debilitating disease with a complex phenotype, remains elusive. Associations with infectious diseases and autoimmune and neuropsychiatric disorders have been observed, without the identification of mechanisms. Previous studies suggest that genetic predisposition plays a role, but results are difficult to replicate, with Genome-Wide Association Studies of ME/CFS being challenging due to the relative rareness and heterogeneity of the disorder...

• Nightsong
• dcc genetics gwas me/cfs wes whole exome sequencing
• Replies: 62
• Forum: ME/CFS research

• 

 

[ChronicallyOverIt]

This Netrin-1/DCC has an immune aspect as well:

https://www.mdpi.com/1422-0067/23/1/275

“
Netrin-1 is also involved in the purinergic pathway, as it binds to the adenosine receptor Adora2b (A2BAR) [13,14,15]. By binding to A2BAR, netrin-1 increases intracellular cAMP levels, which can enhance the endothelial barrier function [13] and macrophage polarization [16]. However, it is of importance that the overall consequences of elevated cAMP levels are opposing in different cell types and organs [17,18]. Moreover, netrin-1 was shown to mediate epithelial cell adhesion and migration through the integrins α6β4 and α3β1 [19].
In 2005, Ly et al. [20] provided the earliest evidence that, outside the central nervous system, netrin-1 can also modulate the migration of granulocytes, monocytes, and leukocytes in and outside the inflamed tissue. Later it was shown that netrin-1 further promotes macrophage differentiation to an alternative activated phenotype”

 

[forestglip]

Is there a gene DCC thread? On mobile and search isn’t searching…

There is now: Genetics: Chromosome 18, DCC