Gene discovery and biological insights into anxiety disorders from a large-scale multi-ancestry genome-wide association study, 2025, Friligkou et al

[forestglip]

Gene discovery and biological insights into anxiety disorders from a large-scale multi-ancestry genome-wide association study

Eleni Friligkou, Solveig Løkhammer, Brenda Cabrera-Mendoza, Jie Shen, Jun He, Giovanni Deiana, Mihaela Diana Zanoaga, Zeynep Asgel, Abigail Pilcher, Luciana Di Lascio, Ana Makharashvili, Dora Koller, Daniel S. Tylee, Gita A. Pathak & Renato Polimanti

[Line breaks added]

Abstract
We leveraged information from more than 1.2 million participants, including 97,383 cases, to investigate the genetics of anxiety disorders across five continental groups.

Through ancestry-specific and cross-ancestry genome-wide association studies, we identified 51 anxiety-associated loci, 39 of which were novel. In addition, polygenic risk scores derived from individuals of European descent were associated with anxiety in African, admixed American and East Asian groups.

The heritability of anxiety was enriched for genes expressed in the limbic system, cerebral cortex, cerebellum, metencephalon, entorhinal cortex and brain stem.

Transcriptome-wide and proteome-wide analyses highlighted 115 genes associated with anxiety through brain-specific and cross-tissue regulation.

Anxiety also showed global and local genetic correlations with depression, schizophrenia and bipolar disorder and widespread pleiotropy with several physical health domains.

Overall, this study expands our knowledge regarding the genetic risk and pathogenesis of anxiety disorders, highlighting the importance of investigating diverse populations and integrating multi-omics information.

Link (Nature Genetics) [Paywall]

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Requested to be posted by @Utsikt.

 

[Utsikt]

Thank you!

Full text is available here:

Gene Discovery and Biological Insights into Anxiety Disorders from a Large-Scale Multi-Ancestry Genome-Wide Association Study - PMC

We leveraged information from more than 1.2 million participants, including 97,383 cases, to investigate the genetics of anxiety disorders across five continental groups. Ancestry-specific and cross-ancestry genome-wide association studies ...

pmc.ncbi.nlm.nih.gov

 

[Utsikt]

I found this study when googling about genetics for anxiety based on a discussion here:

Anxiety also showed global and local genetic correlations with depression, schizophrenia and bipolar disorder and widespread pleiotropy with several physical health domains.

I’m interested in this part, but I don’t think I understand it. It’s discussed in the section called «Pleiotropy with Human Traits and Diseases».

 

[Jonathan Edwards]

Pleiotropy with genes tends to mean that the gene can confer more than one trait and particularly apparently unrelated traits. So a gene that made you more likely to have diabetes and perfect pitch might be called pleiotropic. In evolutionary biology a gene that encodes for a male trait and also for a female liking for that trait is called pleiotropic.

 

[Utsikt]

Pleiotropy with genes tends to mean that the gene can confer more than one trait and particularly apparently unrelated traits. So a gene that made you more likely to have diabetes and perfect pitch might be called pleiotropic. In evolutionary biology a gene that encodes for a male trait and also for a female liking for that trait is called pleiotropic.

Would that mean that the presence of a gene associated with anxiety in a GWAS for another disease isn’t really much evidence that anxiety is involved in the other disease?

 

[Trish]

The wikipedia article on pleiotropy may help. I've skimmed it, it looks interesting.

Pleiotropy - Wikipedia

en.wikipedia.org

 

[Jonathan Edwards]

Would that mean that the presence of a gene associated with anxiety in a GWAS for another disease isn’t really much evidence that anxiety is involved in the other disease?

Absolutely, genetic associations are powerful evidence for causation but may provide little or no information about how that is mediated.

 

[Utsikt]

Absolutely, genetic associations are powerful evidence for causation but may provide little or no information about how that is mediated.

Good to know!

 

[Jonathan Edwards]

Nevertheless, there are certain gene products that as far as we know only do one thing.
Particularly in the immune system.
Then, the mediation may be more transparent!

 

[Utsikt]

Nevertheless, there are certain gene products that as far as we know only do one thing.
Particularly in the immune system.
Then, the mediation may be more transparent!

Could it be that we have not discovered the other uses for that particular gene? Or are the use cases so highly specific that it’s unlikely that they also play a significant role in other traits?

 

[Jonathan Edwards]

Could it be that we have not discovered the other uses for that particular gene? Or are the use cases so highly specific that it’s unlikely that they also play a significant role in other traits?

No doubt one could discuss that for hours, but you would need suitable refreshment to go with it.

 

[forestglip]

Just copying their findings from the supplementary tables so the genes come up in forum searches. For the snps, I converted them to the genes they map to with dbSNP's API.

Variants

We identified 35 linkage disequilibrium (LD)-independent (r2<0.1) variants with genome-wide significant association (p<5×10−8) with ANX (Figure 3; Supplemental Table 3). A conditional analysis yielded five additional genome-wide significant (GWS) variants, leading to a total of 40 genome-wide significant independent SNPs (Supplemental Table 3).

Spoiler: SNPs

'rs7552924': ['PDE4B'],
'rs6689226': [],
'rs10171148': [],
'rs13409451': ['ARHGAP15'],
'rs16839724': [],
'rs6760444': [],
'rs7625233': [],
'rs11128896': [],
'rs13064780': ['IHO1'],
'rs2271961': ['TRAIP'],
'rs2284351': ['ITIH1'],
'rs10078721': [],
'rs4476748': [],
'rs36092177': ['ZSCAN12'],
'rs28381344': ['MSH5', 'MSH5-SAPCD1'],
'rs4870060': ['ESR1'],
'rs3889573': ['MAD1L1', 'LOC100127955'],
'rs55893771': ['MAD1L1'],
'rs8180817': ['FOXP2'],
'rs35704262': ['RABEPK'],
'rs1565418': ['SORCS3'],
'rs4582964': ['LINC02758'],
'rs7129727': ['TMX2', 'TMX2-CTNND1'],
'rs2298527': ['NCAM1'],
'rs2734849': ['ANKK1'],
'rs7928017': [],
'rs75059851': ['IGSF9B'],
'rs4772087': ['STK24'],
'rs56294784': ['STK24'],
'rs56321769': ['LRFN5'],
'rs10138360': ['YLPM1'],
'rs11629241': [],
'rs4702': ['FES', 'FURIN'],
'rs7187913': ['ZFHX3'],
'rs11867537': ['BPTF'],
'rs77363699': ['CCDC178'],
'rs12607755': ['CELF4'],
'rs17408393': ['DCC'],
'rs12457101': ['RAB27B'],
'rs2425752': ['NCOA5']

Transcription

Initially, we conducted a tissue-specific TWAS considering 13 brain tissues available from GTEx v8. We observed 152 transcriptome-wide significant associations related to 39 genes accounting for the number of genes and brain tissues tested (N=165,710, p<3.0×10−7) with a Bonferroni correction (Supplemental Table 9).

Spoiler: Genes

ITIH3
CSNK2B
ITIH1
GNL3
SCAI
NT5DC2
MSH5
CD40
ACYP1
PLCL2
SLC12A5
STK24
GPANK1
SELENOH
GLYCTK
TWF2
LRFN5
CELF4
PBRM1
ZSCAN9
CNNM2
NEK4
SPCS1
TLR9
VARS
CGREF1
RP11-147L13.13
CTD-2334D19.1
FURIN
AC145343.2
ANKK1
SAPCD1
PPP6C
ZDHHC5
C6orf48
SMIM4
GLT8D1
DRD2
LINC01623

After Bonferroni correction accounting for the number of genes tested (N=22,045; p<2.3×10−6), we identified 94 loci with genetically regulated transcriptomic associations with ANX (Figure 3, Supplemental Table 10).

Spoiler: Genes

MED19
SAPCD1
CTNND1
C6orf48
DDAH2
IGSF9B
CD40
PLCL2
HIST1H2AJ
ZBTB12
NCOA5
UBA7
DNAH1
ZDHHC5
YLPM1
TRAF3
SEMA3F
AGBL5
HCG11
CDHR4
FAM120A
SMIM4
NEK4
HIST1H2BK
NT5DC2
ZSCAN9
PBRM1
RNF123
GNL3
AC145343.2
CNNM2
CTB-31N19.5
ZBTB22
RAB27B
TMEM214
LINC01012
PDE4B
HSPA5
OST4
NICN1
ITIH1
BTN2A1
DRD2
GLT8D1
BTN3A1
HIST1H4I
ANKK1
SLC12A5
VARS
STK24
WDR82
FAM180B
MICB
PRSS16
LINC01623
EHMT2
MSH5
CLP1
MADD
KHK
CELF4
ITIH3
SELENOH
XXbac-BPG248L24.13
FURIN
GLYCTK
RP11-384F7.2
TMX2
SCAI
AREL1
CYP21A2
C17orf58
C2
FCF1
CTA-14H9.5
RABEPK
YPEL4
FAM212A
ZNF184
TFAP2B
PPM1M
CSNK2B
PPP6C
CELF1
TWF2
LINC01360
RP11-6N13.1
EMILIN1
TLR9
CTD-2334D19.1
MAPRE3
IP6K1
GPANK1
LRFN5

Proteins

We identified 24 loci with evidence of genetically regulated proteomic association with ANX after Bonferroni correction accounting for the number of genes tested (N=1,629; p<3.1×10−5) (Figure 3; Supplemental Table 11).

Spoiler: Genes

DOC2A
SLC25A12
NEK4
GMPPB
DPYSL5
BTN2A1
PLCG1
BTN3A3
FLOT2
GPT
GPX1
RAB27B
KHK
MKRN1
TPBG
CCDC92
B3GALTL
CTNND1
CGREF1
PDE1A
PBXIP1
RAB5C
CNNM2
GDI2

 

[Turtle]

What would we do without you, @forestglip?
My brain can only remember a handful. The ones with a vowel.

 

[forestglip]

I searched for any results on S4ME for the genes associated with SNPs above. Here are the ones with matches:

PDE4B

• Dissecting the genetic complexity of myalgic encephalomyelitis/chronic fatigue syndrome via deep learning-powered genome analysis, 2025, Zhang+
• Evidence of shared genetic factors in the etiology of gastrointestinal disorders and endometriosis…, 2023, Yang et al.

ITIH1

• Proteomic analysis of post-COVID condition: Insights from plasma and pellet blood fractions, 2024, Seco-González et al

ESR1

• Mild SARS-CoV-2 infection modifies DNA methylation of peripheral blood mononuclear cells from COVID-19 convalescents, 2021, Huomen et al
• A novel estrogen receptor 1: sphingomyelin phosphodiesterase acid-like 3B pathway mediates rituximab response in myositis patients, 2022, Parkes et al
• Integrative Multi-Omics Framework for Causal Gene Discovery in Long COVID, 2025, Le et al

TMX2

• Genome-wide analyses identify 30 loci associated with obsessive–compulsive disorder, 2025, Strom et al.

NCAM1

• Genome-wide analysis of 53,400 people with irritable bowel syndrome highlights shared genetic pathways with mood and anxiety disorders, 2021, Eijsbout

FURIN

• A lot of search results

ZFHX3

• Upregulation of olfactory receptors and neuronal-associated genes highlights complex immune and neuronal dysregulation in [LC], 2025, Shahbaz+

BPTF

• Preprint Long COVID Risk Loci Implicated from Genome-Wide Association Studies of COVID-19 Susceptibility and Hospitalization, 2025, Cheng
• Multi-ancestry GWAS of [LC] identifies immune-related loci and etiological links to [CFS], fibromyalgia and depression, 2024, Chaudhary et al
  

RAB27B

• Organ and cell-specific biomarkers of Long-COVID identified with targeted proteomics and machine learning, 2023, Patel et al