Genome-wide association study meta-analysis of suicide death and suicidal behavior, 2022, Li et al

[forestglip]

Genome-wide association study meta-analysis of suicide death and suicidal behavior

Qingqin S. Li, Andrey A. Shabalin, Emily DiBlasi, Srihari Gopal, Carla M. Canuso, FinnGen, International Suicide Genetics Consortium, Aarno Palotie, Wayne C. Drevets, Anna R. Docherty & Hilary Coon

Published: 17 October 2022

[Line breaks added]

Abstract
Suicide is a worldwide health crisis. We aimed to identify genetic risk variants associated with suicide death and suicidal behavior. Meta-analysis for suicide death was performed using 3765 cases from Utah and matching 6572 controls of European ancestry. Meta-analysis for suicidal behavior using data across five cohorts (n = 8315 cases and 256,478 psychiatric or populational controls of European ancestry) was also performed.

One locus in neuroligin 1 (NLGN1) passing the genome-wide significance threshold for suicide death was identified (top SNP rs73182688, with p = 5.48 × 10−8 before and p = 4.55 × 10−8 after mtCOJO analysis conditioning on MDD to remove genetic effects on suicide mediated by MDD). Conditioning on suicidal attempts did not significantly change the association strength (p = 6.02 × 10−8), suggesting suicide death specificity.

NLGN1 encodes a member of a family of neuronal cell surface proteins. Members of this family act as splice site-specific ligands for beta-neurexins and may be involved in synaptogenesis. The NRXN-NLGN pathway was previously implicated in suicide, autism, and schizophrenia.

We additionally identified ROBO2 and ZNF28 associations with suicidal behavior in the meta-analysis across five cohorts in gene-based association analysis using MAGMA. Lastly, we replicated two loci including variants near SOX5 and LOC101928519 associated with suicidal attempts identified in the ISGC and MVP meta-analysis using the independent FinnGen samples.

Suicide death and suicidal behavior showed positive genetic correlations with depression, schizophrenia, pain, and suicidal attempt, and negative genetic correlation with educational attainment. These correlations remained significant after conditioning on depression, suggesting pleiotropic effects among these traits. Bidirectional generalized summary-data-based Mendelian randomization analysis suggests that genetic risk for the suicidal attempt and suicide death are both bi-directionally causal for MDD.

Link | PDF (Nature Molecular Psychiatry) [Open Access]

 

[forestglip]

Posting because the NLGN1 gene came up as one of 115 genes predictive of ME/CFS in a recent preprint. (In two places they say "NRGN1", but I think that's a typo and should be NLGN1.)

S4ME thread: Dissecting the genetic complexity of myalgic encephalomyelitis/chronic fatigue syndrome via deep learning-powered genome analysis (2025, Preprint: MedRxiv)

As highlighted in our network analysis, ME/CFS genes participate in biological pathways associated with synaptic function (M20; Fig. 4B and 4D).

SYNGAP1, another gene driving downregulation of the ME/CFS genes in cytotoxic CD4 T cells (Fig. 4G) and a member of M20, is involved in synaptic signaling and plasticity, essential for brain function with mutations linked to neurodevelopmental and psychiatric disorders53. SYNGAP1’s role in synaptic signaling highlights its potential connection to neurological symptoms in ME/CFS, offering therapeutic potential in neuroprotective strategies54.

Neuroligins NLGN1 and NLGN255, DLG256, GRM157, and the DLGAP family including DLGAP1, DLGAP2, DLGAP3, and DLGAP458 are proteins that regulate synaptic function and glutaminergic synaptic function in particular. Both the neuroligins and the DLGAP proteins are postsynaptic proteins with a role in synapse organisation59. Neuroligins bind to presynaptic neurexins and have a role in synapse specification.

This entire set of synaptic genes has been linked to various neuropsychiatric disorders including clinical depression59. NRGN1 was the only genome-wide significant hit in a GWAS of suicide behaviour that is linked to major depression60. A truncating LoF mutation within NRGN1 has been linked to depression in the context of familial Alzheimer’s disease61.

Most prominently, this set of synaptic genes is implicated in attention deficit hyperactivity disorder (ADHD) and autistic spectrum disorder (ASD) (Wikipathways WP5420). Indeed the entire set of ME/CFS genes is significantly enriched in this pathway (P = 3.9 × 10−10, two-sided Fisher’s exact test). A shared genetic basis between ME/CFS and ADHD/ASD suggests that these two disorders may have shared aspects of molecular dysfunction. It is intriguing that the typical age of onset of ADHD/ASD is in childhood whereas ME/CFS typically manifests in adolescence or adulthood62. If both disorders share a related mechanism then perhaps they are age-specific manifestations of a similar underlying process.

Reference 60 in the quote is this thread's study.

 

[forestglip]

Among the genes associated with SD [suicide death], NLGN1 encodes a member of a family of postsynaptic neuronal cell surface proteins. Members of this family act as splice site-specific ligands for presynaptic β-neurexins and are involved in the formation and remodeling of central nervous system synapses [65, 66].

Another variant in NLGN1 (weak LD with the variant reported herein) is associated with SA [suicidal attempt] in the ISGC and MVP meta-analysis, suggesting allelic heterogeneity in this gene.

Neurexin 1 variants were previously implicated as risk factors for SD [67, 68]. The top associated variant rs73182688 in NLGN1 in this study is nominally associated with BMI (p = 0.0006), depression (p = 0.004 in FinnGen R5), and personality disorder (p = 0.004 in FinnGen R5) (Supplementary Table S21). Other variants (SNVs and CNVs) in NLGN1 and/or other family members NLGN3 and NLGN4 were previously associated with PTSD, autism, obsessive-compulsive disorder, and depression [69,70,71,72,73,74,75].

The rs6779753 variant in NLGN1 associated with PTSD as well as with the intermediate phenotypes of higher startle response and greater hemodynamic responses (assessed using functional MRI) of the amygdala and orbitofrontal cortex to fearful face stimuli was not in LD with the variant identified herein. In our study, rs6779753 was only suggestively associated with SD (p = 0.06).

NLGN1 was also implicated in a preclinical model of depression [76]. In addition, presynaptic neurexins and cytoplasm partners such as SHANK also have been implicated in autism, schizophrenia, and mental retardation [73, 77,78,79,80,81,82,83].

Overall, there is substantial genetic evidence on the NRXN-NLGN pathway in suicide and other psychiatric conditions.

 

[V.R.T.]

Just anecdotally, I have suffered from suicidal ideation since my late teens. It became much worse when I got ME, has become even worse as my severity level has increased, and becomes very intense when I crash.

I'm not sharing for sympathy but because it often feels like a consequence of intense PEM, like something caused by my brain, rather than an environmental thing. I have heard similar things from other pwME/LC.

Perhaps this gene is part of the explanation?

 

[Utsikt]

Just anecdotally, I have suffered from suicidal ideation since my late teens. It became much worse when I got ME, has become even worse as my severity level has increased, and becomes very intense when I crash.

I'm not sharing for sympathy but because it often feels like a consequence of intense PEM, like something caused by my brain, rather than an environmental thing. I have heard similar things from other pwME/LC.

Perhaps this gene is part of the explanation?

That must be so scary! I had suicidal ideations once as a side effect of a drug, it really freaked me out.

 

[V.R.T.]

That must be so scary! I had suicidal ideations once as a side effect of a drug, it really freaked me out.

It is really unpleasant. I have gotten used to the more background level stuff, but to have your brain be like 'no, you need to die' and not even be well enough to call a friend is awful. And to know that you are in dire circumstances and your quality of life really is so awful makes it much harder to talk yourself out of it. It used to be an occasion to break out my guitar and play some Elliott Smith or something equally miserable/cathartic. Or watch a really bleak film. With such things beyond me I just have to sort of ride it out.

In the past when things got that acute it would quite often trigger a big drinking binge so at least I can't go to the pub anymore haha! That's the one positive.

 

[Utsikt]

In the past when things got that acute it would quite often trigger a big drinking binge so at least I can't go to the pub anymore haha! That's the one positive.

The silver linings of our missery!

 

[Yann04]

I agree that it wouldn't suprise me that suicide is linked with ME. Not only have a bunch of studies looked at the link and found significant correlations, (atleast one of them prospective). But we have to remember these are the people diagnosed with the disease, who are far more likely to atleast get some sort of proper care or support.

If we think about the ones who never knew, the vast majority of them probably died sidelined by society. Would not surprise me if the modality was suicide for many of them.

And I agree with @V.R.T. there's probably something physical as well as environmental. The only way I'm able to get through my really bad acute pem that feels like I have a bad allergic reaction + food poisoning + my brain on fire, is basically suicidal idealation until it passes. It's like my brain is primed to think of that when the suffering is that bad. I can't control it, just goes to that place.

("Luckily" I'm not worried I'll do anything about it because when I'm in that bad pem I can't even move)

 

[Saz94]

I couldn't understand all the technical language but it seems to me that if there's a gene linked to suicide, it's most likely due to that gene being linked to mental health problems, or to autism (there are high rates of suicide amongst autistic people due to the difficulties we have in life and the way we are treated by society), or to a horrible disease like ME which can be extremely difficult to live with (compounded by all the ways we are treated by other people/society).

If one wants to prevent suicides, the thing to do is to improve the social conditions so that people are less likely to want to commit suicide. Better care and support for disabled people (incl people with mental health issues), for example.

If you are a geneticist wishing to reduce suicides, try not looking for a suicide gene and instead put your efforts into researching some horrific disease, for instance ME, that people kill themselves over.

 

[forestglip]

Info about neuroligins and one form of neuroligin, neurologin 1 (NLGN1) from Wikipedia:

Neuroligin (NLGN), a type I membrane protein, is a cell adhesion protein on the postsynaptic membrane that mediates the formation and maintenance of synapses between neurons. Neuroligins act as ligands for β-neurexins, which are cell adhesion proteins located presynaptically. Neuroligin and β-neurexin "shake hands", resulting in the connection between two neurons and the production of a synapse.

Neuroligins also affect the properties of neural networks by specifying synaptic functions, and they mediate signalling by recruiting and stabilizing key synaptic components.

Neuroligins interact with other postsynaptic proteins to localize neurotransmitter receptors and channels in the postsynaptic density as the cell matures.[3]

Additionally, neuroligins are expressed in human peripheral tissues and have been found to play a role in angiogenesis [blood vessel formation].[4]

The extracellular domain of NLGN consists mostly of a region that is homologous to acetylcholinesterases, but the amino acids important for catalysis in AChE are not conserved in NLGN, which lack esterase activity. Furthermore, this AChE homologous region is crucial for the proper function of NLGN.[2]

Neuroligin 1 is expressed specifically in the CNS at excitatory synapses.

Neuroligin 1 localizes at excitatory synapses, neuroligin 2 at inhibitory synapses and neuroligin 3 at both. Reduction in the levels of neuroligins 1, 2 and 3 results in a strong reduction of inhibitory input but little reduction in excitatory input.[14]

This might be a reach, but if neuroligin mutations might be causal for things like psychiatric disorders and ME/CFS, and considering neuroligin has a portion that looks very similar to acetylcholinesterase, could this be related to the associations of acetylcholinesterase inhibitors with conditions like gulf war illness and psychiatric disorders?

Maybe these chemicals are capable of disturbing neuroligin function in a similar way to these mutations, leading to similar conditions?

Potential links to cholinesterase-inhibiting chemicals in both gulf war illness and psychiatric disorders.

Acetylcholinesterase inhibitor exposures as an initiating factor in the development of Gulf War Illness, a chronic neuroimmune disorder in deployed veterans, Michalovicz et al, July 2020

Depressive symptoms and suicide attempts among farmers exposed to pesticides, Zheng et al, June 2024