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

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]

 

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)

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

 

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.

 

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.

 

The silver linings of our missery!

 

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)

 

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.

 

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

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?