Genetics: NEGR1

Jonathan Edwards

Jonathan Edwards

Senior Member (Voting Rights)
A quick look on AI.

The
NEGR1 (Neuronal Growth Regulator 1) gene, located on chromosome 1p31.1, encodes a GPI-anchored cell adhesion molecule critical for brain development, synaptic organization, and neuronal connectivity. Strongly associated with obesity, depression, and neurodevelopmental disorders, NEGR1 regulates energy balance and synaptic plasticity. Studies suggest it plays a role in cognitive, emotional, and social behaviors.

Key Aspects of the NEGR1 Gene:
  • Function: As part of the IgLON family (including LSAMP, OPCML, NTRA, IGON5), NEGR1 acts as a cell adhesion molecule in the nervous system. It is involved in regulating synapse assembly, cholesterol homeostasis, and axon growth.
  • Disease Associations:
    • Obesity: Multiple GWAS studies consistently link NEGR1 variants with body mass index (BMI).
    • Neuropsychiatric/Developmental: NEGR1 deletions or dysfunction are linked to intellectual disability, developmental delays, autism spectrum disorder (ASD), dyslexia, anxiety, and depression.
    • Neurobiology: Deficiency in mice leads to altered dopamine/serotonin systems, reduced locomotor activity, and impaired social behavior.
    • Mechanism: It works as a trans-neural growth-promoting factor and is involved in modulating synaptic plasticity, particularly in corticolimbic circuits.
    • Expression: Predominantly expressed in the brain, including the hypothalamus, cortex, and hippocampus.
 
Looking at the gene cards for the non coding elements a number of these seem to be promoters/enhancers related to NEGR1. I guess not surprising given the proximity. But could here be something here (and potentially with other variants or near misses on significance) which means we’re seeing some, perhaps tissue specific, effects of relevant genes up or down regulated?

These can be seen in the relevant area on LocusZoom by toggling to show all features. But since I have new toys I ran them on the DecodeME data around NEGR1, lowering the significance threshold and looking specifically at the area of interest, which resulted in

ENSG00000225087
ENSG00000280317
KRT8P21
LINC01360
LINC02238
LINC02796
RN7SKP19
RNA5SP50
RNU6-1246P
 
NEGR1 deficiency disrupts lipid metabolism and steroidogenesis in Leydig cells, linking testosterone to behavior (2025)

Neuronal growth regulator 1 (NEGR1) has been identified as a critical risk factor for major depressive disorders in humans. Although NEGR1 is predominantly expressed in the brain, its deletion in mice (Negr1−/−) results in abnormalities in peripheral tissues, suggesting a role beyond the nervous system, particularly in intracellular lipid trafficking. However, the role of NEGR1 in testosterone production has not yet been elucidated.

Here, we demonstrate that Negr1−/− mice exhibit significantly reduced serum and testicular testosterone levels, accompanied by diminished male reproductive behaviors. The expression of key testosterone-synthesizing enzymes was downregulated in Leydig cells, and histological analysis revealed disorganized testicular and epididymal structures with lipid droplet accumulation in testicular cells. Additionally, Negr1−/− mice displayed a significant increase in abnormal sperm morphology. Notably, testosterone supplementation alleviated their impaired sexual behaviors and mitigated anxiety- and depression-like phenotypes.

These findings highlight a crucial role for NEGR1 in testicular function, particularly in testosterone production and spermatogenesis, underscoring the intricate link between hormonal balance and mental health.

Web | PDF | Journal of Lipid Research | Open Access

As NEGR1 is highly expressed in the cerebral cortex and hippocampus of the adult brain, its neuronal function became a subject of interest when a GWAS discovered NEGR1 as a locus associated with human obesity. However, the findings that Negr1 − /− mice show abnormalities in peripheral tissues such as increased adiposity, hepatic fat accumulation, and muscle atrophy, and NEGR1 interacts with lipid carriers in adipocytes, support the concept that NEGR1 has non-neuronal functions in lipid transport and metabolism in peripheral organs.
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Here, we show that NEGR1 deficiency causes pronounced lipid droplet accumulation in testicular cells, reduced expression of steroidogenic enzymes, and markedly decreased serum and testicular testosterone levels. The elevated expression of genes related to lipid uptake and storage further supports the conclusion that NEGR1 is essential for efficient cholesterol mobilization in the testes. Among testicular cells, Leydig cells have a particularly high demand for intracellular cholesterol to sustain testosterone synthesis, and appear especially vulnerable to this defect. NEGR1 loss likely leads to serious stagnation of free endosomal cholesterol—the genuine precursor of steroids—ultimately impairing steroidogenesis and spermatogenesis.
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In conclusion, this study identifies NEGR1 as a previously unrecognized regulator of cholesterol trafficking and testosterone biosynthesis in Leydig cells. By impairing lipid mobilization, NEGR1 deficiency disrupts steroid hormone production, spermatogenesis, and testicular architecture, with secondary systemic effects on reproductive and affective behaviors. These results expand NEGR1’s functional significance beyond the nervous system, highlighting its broader role in lipid metabolism within peripheral tissues and its potential relevance to disorders linking metabolic, reproductive, and neuropsychiatric domains.
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Is it possible to link poor functioning NEGR1 gene to the loss of the CHR neurons?

Edit: I asked Gemini, and it’s so far outside my knowledge I don’t know if I just got slop back:

“
Summary of the Hypothesis


While there is likely no direct paper linking NEGR1 to this specific ME/CFS autopsy result yet (as the findings are very new), the biological logic follows a clear path:


1. ME/CFS Finding: CRH neurons in the PVN are depleted.


2. NEGR1 Function: NEGR1 maintains the structural integrity and synaptic connections of neurons in the PVN.


3. Theoretical Mechanism: A failure in NEGR1 could cause the structural collapse of the CRH neural network, leading to the observed depletion of neurons and the subsequent exhaustion (dystrophy) of the microglia trying to save them.”
 
From Wikipedia:

'The PVN is thought to mediate many diverse functions , including osmoregulation, appetite, wakefulness, stress responses, as well as the regulation of social behavior.[2][3][4]'

en.wikipedia.org

Paraventricular nucleus - Wikipedia

en.wikipedia.org en.wikipedia.org

Osmoregulation stuck out to me:

'Osmoregulation is the active regulation of the osmotic pressure of an organism's body fluids, detected by osmoreceptors, to maintain the homeostasis of the organism's water content; that is, it maintains the fluid balance and the concentration of electrolytes (salts in solution which in this case is represented by body fluid) to keep the body fluids from becoming too diluted or concentrated.'

Osmoregulation - Wikipedia

en.wikipedia.org en.wikipedia.org
 
From my understanding a connection between NEGR1 and CD36 exists.

https://pubmed.ncbi.nlm.nih.gov/35526561/

Interestingly, CD36 was mentioned by Hanson at this post by @Hutan

https://www.s4me.info/threads/alter...ue-syndrome-2023-maya-et-al.31598/post-457163

Here is the study : https://www.mdpi.com/1422-0067/24/3/2010


which says :


Nevertheless, we see a lower abundance of the cell membrane fatty acid transporter, CD36, in the same ME/CFS cell samples in circulation and after activation compared to healthy cells (Figure 4C). Thus, while ME/CFS NK cells exhibit increased levels of FAO in the mitochondria, CD36-mediated uptake into cells does not appear to factor in the differences between NK cells from cases vs. controls.
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Also from my understanding, NEGR1 alterations involve increased levels am I correct? If this is indeed true, then this leads to decreased CD36 levels. And if this is true then in the following figure we have yet one more potential target, namely CD36 (annotated in green arrows). MerTK has also been identified as a key target for COVID19 symptom severity : https://pmc.ncbi.nlm.nih.gov/articles/PMC9238057/



Screenshot 2026-02-13 at 14.03.56.png
 
Jonathan Edwards said:
So do we have any information about the possible link to NEGR1 in ME/CFS in terms of where the relevant (different) SNPs would have altered expression. I am doubtful one could draw any sensible conclusion but it might be interesting.
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forestglip said:
No, they didn't look at gene expression linked to the SNPs near NEGR1 because that locus didn't quite reach genome-wide significance.
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Seems like NEGR1 was mentioned in a Depression GWAS.


I think it was even less than 'the locus didn't quite reach genome-wide significance' in DecodeME. If we are going to look at genes with hits with a p value y axis of 4 or more, I think we'll be considering a very large percentage of human genes.
 
Hutan said:
Remind me, why are we interested in NEGR1? It doesn't look very relevant from that DecodeME plot.
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That plot includes lots of non-coding RNA. This one shows NEGR1 and LRRIQ3 are the closest coding genes to this locus.
forestglip said:
negr1_2.png
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NEGR1 is interesting because there seems to be growing evidence that it is relevant in depression and anxiety disorders, though it seems like the causal variant is different from ME/CFS. Just a gene to watch, in case its mechanism of pathology is figured out in other conditions.

Edit: Also, NEGR1 (neuronal growth regulator 1) seems related to the nervous system/synapses, which could make it a good candidate if we think ME/CFS is related to the nervous system too.
May be involved in cell-adhesion. May function as a trans-neural growth-promoting factor in regenerative axon sprouting in the mammalian brain
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And so people are assuming that those hits between 73.00 and 73.50 are affecting the expression of the NEGR1 gene.
How much of a long shot is that? Is it just clutching at straws?

Is it at least as likely that the hits are affecting other genes? For example, KRT8P21 is in that range of peaks - below the purple diamond.


1770571477104.png



KRT8P21 is a pseudogene that has been found to be associated in a small GWAS with kidney disease in Chinese women.

In addition, we found two suggestive loci associated with eGFRcr-cys on chromosome 1(1p31.1) and ..., whose lead SNPs were rs66588571(P=3.14E-06) and ... They were located in intergenic regions near the KRT8P21 and ..., respectively.
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Secondly, we found the lead SNP rs66588571 in 1p31.1, which mapped genes including CRYZ, TYW3, etc. It has been observed that CRYZ is highly expressed in the renal collecting ducts [47]. CRYZ and TYW3 were also found to be related to resistin levels [48]. Our study also enriched pathways associated with resistin levels and body mass index, which have been consistent with previ-ous studies. Resistin is a cysteine-rich cytokine secreted by fat cells [49]. The study found that circulating resistin levels were significantly elevated in patients with renal impairment [50–53]. Studies have shown that the increase of resistin can induce the secretion of inflammatory cytokines such as tumor necrosis factor α (TNF-α)[54], and resistin can significantly increase the expression of endothelin (ET)-1 [55, 56] and monocyte chemotactic protein (MCP)-1(a mediator of inflammation) [55], the overexpression of these substances will cause inflamma-tion, lead to glomerular sclerosis and renal tubulointerstitial fibrosis, thus affecting kidney function.
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The authors claim that that SNP near KRT8P21 maps to genes including CRYZ and TYW3. I have even more doubts about that. But, my point is that they didn't immediately jump to assuming that that SNP (which is in the range of the DecodeME Chromosome 1 hits) is impacting on the NEGR1 gene.

It is feeling a bit like astrology - you can always find something that seems to fit. I'm trying to get a sense of how much those Chromosome 1 DecodeME hits currently tell us, and how reasonable it is to assume that a neighbouring gene is impacted.
 
@Hutan I agree with your overall point though I'd maybe say the game we played here was telephone rather than straws. I think how we got here is forestglip made a post early on in the DecodeME thread about NEGR1, noting it was the closest gene to this SNP.
forestglip said:
NEGR1 appears to be the closest gene
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Once NEGR1 popped up in a couple other GWAS I guess it sounded interesting enough to make a thread about.

It might be good if we organized all our gene threads like you did yours (eg OLFM4) with a message at the beginning explaining what inspired us to look at it / what the evidence is? That way it could be clear if the evidence is especially speculative.

To try and figure out if the nearby SNP highlighted by DecodeME actually has anything to do with NEGR1 I am way out of my depth but I guess we might want to try something more advanced, like the promotor/enhancer stuff @hotblack is looking into, or the fancy TWAS thing forestglip talked about in that other thread?
 
I looked at the promoter and enhancer info from my scripts and few really jumped out, the hits are off in the direction you’d expect of a promoter, but don’t match any identified, but rather the location of lots of other non protein coding RNA, so not sure what to make of this either.

Edit: I’m pulling together all the info for all these candidates so people can explore more easily, will hopefully have more to share soon so people can investigate.
 
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hotblack said:
the hits are off in the direction you’d expect of a promoter
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Could you spell this out a bit more for my slow brain:
Are you saying you looked around NEGR1 and found DecodeME hits (ie. SNPs with relatively low p-value?) in locations where it would make sense for a promotor or enhancer to be, though none have been identified there yet by researchers?
 
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