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

SNT Gatchaman

SNT Gatchaman

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Genome-wide analyses identify 30 loci associated with obsessive–compulsive disorder
Strom, Nora I. and 207 others

Obsessive–compulsive disorder (OCD) affects ~1% of children and adults and is partly caused by genetic factors. We conducted a genome-wide association study (GWAS) meta-analysis combining 53,660 OCD cases and 2,044,417 controls and identified 30 independent genome-wide significant loci.

Gene-based approaches identified 249 potential effector genes for OCD, with 25 of these classified as the most likely causal candidates, including WDR6, DALRD3 and CTNND1 and multiple genes in the major histocompatibility complex (MHC) region. We estimated that ~11,500 genetic variants explained 90% of OCD genetic heritability. OCD genetic risk was associated with excitatory neurons in the hippocampus and the cortex, along with D1 and D2 type dopamine receptor-containing medium spiny neurons.

OCD genetic risk was shared with 65 of 112 additional phenotypes, including all the psychiatric disorders we examined. In particular, OCD shared genetic risk with anxiety, depression, anorexia nervosa and Tourette syndrome and was negatively associated with inflammatory bowel diseases, educational attainment and body mass index.

Link | PDF (Nature Genetics) [Open Access]
 
The most significant SNP (rs78587207 (P = 5.28 × 10−12)) identified in the GWAS is located on chr11q12.1 and has been previously associated with several traits, including neuropsychiatric phenotypes such as depressive symptoms and neuroticism. Gene-based analyses identified four putative causal genes within this locus. The closest gene to rs78587207 is CTNND1, which encodes the cell adhesion molecule p120 catenin. This gene was associated with OCD using three gene-based tests (mBAT-combo, TWAS and PWAS), and we found strong evidence for colocalization of the TWAS signal for CTNND1 in the dlPFC. The dlPFC has been consistently implicated in the neural circuitry of OCD as well as in compulsivity more broadly as part of the cortico–striatal–thalamo–cortical circuitry. The protein product of CTNND1 is a regulator of cell–cell adhesion and has a crucial role in gene transcription, Rho GTPase activity and cytoskeletal organization.
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Other credible causal genes in the locus include CLP1 (cleavage factor polyribonucleotide kinase subunit 1), TMX2 (thioredoxin-related transmembrane protein 2) and ZDHHC5 (zinc finger DHHC type palmitoyltransferase 5). Rare genetic mutations CLP1 are associated with pontocerebellar hypoplasia type 10, a very rare autosomal recessive neurodegenerative disease characterized by brain atrophy and delayed myelination resulting in intellectual disability. TMX2 is associated with increased risk of neurodevelopmental disorders with microcephaly, cortical malformations, spasticity and congenital nervous system abnormalities. ZDHHC5 is broadly expressed in the brain, including the frontal cortex.
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We identified a total of 25 credible causal genes based on robust evidence using multiple positional and functionally informed gene-based approaches. Notably, DLGAP1, which has been previously implicated in OCD pathogenesis, was not identified in either the GWAS or in the gene-based analyses.
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(DLGAP1 was one of the top hits in Dissecting the genetic complexity of myalgic encephalomyelitis/chronic fatigue syndrome via deep learning-powered genome analysis)

Four other genes identified through these analyses are located in the MHC locus, a region on chromosome 6 that has a major role in the adaptive immune system and has been repeatedly linked to major psychiatric disorders. The newly identified MHC association for OCD is noteworthy given evidence linking OCD with autoimmune disorders. Genetic pleiotropy may underlie this connection, with variants predisposing individuals to both autoimmune conditions and OCD. Furthermore, some OCD subtypes, such as pediatric acute-onset neuropsychiatric disorders associated with Streptococcus and pediatric acute-onset neuropsychiatric syndrome, may have autoimmune origins. Nevertheless, we were surprised to discover several negative genetic correlations between OCD and autoimmune disorders such as Crohn’s disease, ulcerative colitis and inflammatory bowel disease in our analyses, suggesting that there is heterogeneity (and perhaps pleiotropy) in the genetic relationships between autoimmune disorders and OCD.
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InitialConditions said:
Conversation article here: https://theconversation.com/researc...-how-it-changes-the-brain-new-research-255572
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Woah from this article:

"Additionally, we found that certain types of brain cells – particularly medium spiny neurons in a brain region called the striatum – were strongly linked to the OCD genes we identified. Medium spiny neurons play an important role in habit formation, the process by which a behavior becomes automatic and habitual – think compulsions. Specific receptors on medium spiny neurons are common targets for medications that are sometimes used to help treat OCD."

These things keep popping up!
 
ChronicallyOverIt said:
Woah from this article:

"Additionally, we found that certain types of brain cells – particularly medium spiny neurons in a brain region called the striatum – were strongly linked to the OCD genes we identified. Medium spiny neurons play an important role in habit formation, the process by which a behavior becomes automatic and habitual – think compulsions. Specific receptors on medium spiny neurons are common targets for medications that are sometimes used to help treat OCD."

These things keep popping up!
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Were there links to MSN for ME/CFS, or just eMSN specifically?
 
V.R.T. said:
What medications are they talking about here?
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Not specified, but it looks like both Dopamine Receptor Antagonists (e.g. Aripiprazole/Abilify, Risperidone/Risperdal, and Quetiapine/Seroquel) and Glutaminergic modulators (e.g. Memantine/Namenda, Riluzole/Rilutek, and Topiramate/Topamax) would fit this description. That's just from a quick search, mind you, not my own knowledge.

As yet another of the pwME here with a pre-existing OCD diagnosis (but to date unmedicated), I am certainly interested in seeing whether this connection has anything to it.
 
Utsikt said:
Were there links to MSN for ME/CFS, or just eMSN specifically?
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I believe just eMSN. I've confused the two at least a dozen times already and expect to do it a lot more. That said, since eMSN are such a small subset (and not as well known?) it might be worth checking papers that mention MSN to see if some of the MSN have both D1 and D2 type receptors or other eMSN makers ?
 
DHagen said:
it looks like both Dopamine Receptor Antagonists (e.g. Aripiprazole/Abilify, Risperidone/Risperdal, and Quetiapine/Seroquel) and Glutaminergic modulators (e.g. Memantine/Namenda, Riluzole/Rilutek, and Topiramate/Topamax) would fit this description
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Both medications that some pwME report improvement on iirc. Definitely LDA but i thought maybe the glutamenergic ones too?


DHagen said:
As yet another of the pwME here with a pre-existing OCD diagnosis (but to date unmedicated), I am certainly interested in seeing whether this connection has anything to it.
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Yeah same and same.
 
DHagen said:
Given that eMSN are a subgroup of MSN, and that we're talking about D1/D2 receptors in all cases, that doesn't necessarily mean that this connection is irrelevant though, does it?
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Yes, possibly??

I have asked here if it is possible to do a comparison of the OCD data and DecodeME data:
ChronicallyOverIt

Post in thread 'Eccentric medium spiny neuron (eMSN)'

ME/CFS Science Blog said:
I've combined the MAGMA analysis that Duncan et al. 2025 did for other diseases and the analysis @tralfamadorian97 did for ME/CFS using the 461 cell type cluster in the human brain analysis. I've coloured the signals for eMSN (clusters 222-234 and cluster 426) in red.
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@tralfamadorian97 or @ME/CFS Science Blog would it be useful to do one of these for the OCD data vs ME/CFS?
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DHagen said:
Given that eMSN are a subgroup of MSN, and that we're talking about D1/D2 receptors in all cases, that doesn't necessarily mean that this connection is irrelevant though, does it?
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Apparently, the genetic profile of eMSN is very distinct from the genetic profile of MSN.

So while they share some aspects, I’m not sure we can assume that just because one is involved the other might be.

If there is no signal for MSN in ME/CFS, we might actually want to figure out the differences instead of the similarities.
 
Utsikt said:
Apparently, the genetic profile of eMSN is very distinct from the genetic profile of MSN.

So while they share some aspects, I’m not sure we can assume that just because one is involved the other might be.

If there is no signal for MSN in ME/CFS, we might actually want to figure out the differences instead of the similarities.
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Thank you! I have been following that thread and, while there was some kind of tingling in the back of my brain, I either missed or, far more likely, forgot that particular point.

If we are looking for overlap (and maybe there's no sign of this), it would also be important to know whether eMSN play a role in OCD - particularly given how new awareness of eMSN actually is, would this group have looked for them?
 
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