Scots scientists uncover DNA 'switch' which affects anxiety levels

[Amw66]

https://news.stv.tv/north/universit...ts-identify-area-of-dna-that-controls-anxiety

Professor Mackenzie explains their novel approach to anxiety research.

He said: “We already know that 95% of the genetic differences associated with disease are found outside of protein coding genes.

“This part of the genome, known as the “non-coding genome” has not been well explored because we previously lacked the tools to do so.

“We also know that the non-coding genome contains information in the form of gene switches that tell genes where and when to be turned on.

“This is important as genes have to be switched on in the right cells and at the right times to ensure good health and when they are not turned on correctly can contribute to conditions like anxiety, depression and addiction.

“These areas of the non-coding genome are what we study in our lab.”

 

[SNT Gatchaman]

An ancient polymorphic regulatory region within the BDNF gene associated with obesity modulates anxiety-like behaviour in mice and humans
McEwan, Andrew R.; Hing, Benjamin; Erickson, Johanna C.; Hutchings, Greg; Urama, Charity; Norton-Hughes, Emily; D’Ippolito, Mariam; Berry, Susan; Delibegovic, Mirela; Grassmann, Felix; MacKenzie, Alasdair

Obesity and anxiety are morbidities notable for their increased impact on society during the recent COVID-19 pandemic. Understanding the mechanisms governing susceptibility to these conditions will increase our quality of life and resilience to future pandemics.

In the current study, we explored the function of a highly conserved regulatory region (BE5.1) within the BDNF gene that harbours a polymorphism strongly associated with obesity (rs10767664; p = 4.69 × 10–26). Analysis in primary cells suggested that the major T-allele of BE5.1 was an enhancer, whereas the obesity-associated A-allele was not. However, CRISPR/CAS9 deletion of BE5.1 from the mouse genome (BE5.1KO) produced no significant effect on the expression of BDNF transcripts in the hypothalamus, no change in weight gain after 28 days and only a marginally significant increase in food intake. Nevertheless, transcripts were significantly increased in the amygdala of female mice and elevated zero maze and marble-burying tests demonstrated a significant increase in anxiety-like behaviour that could be reversed by diazepam.

Consistent with these observations, human GWAS cohort analysis demonstrated a significant association between rs10767664 and anxiousness in human populations. Intriguingly, interrogation of the human GTEx eQTL database demonstrated no effect on BDNF mRNA levels associated with rs10767664 but a highly significant effect on BDNF-antisense (BDNF-AS) gene expression and splicing. The subsequent observation that deletion of BE5.1 also significantly reduced BDNF-AS expression in mice suggests a novel mechanism in the regulation of BDNF expression common to mice and humans, which contributes to the modulation of mood and anxiety in both species.

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

 

[rvallee]

Mice these days, always worried and stressed about their marbles. Not like the mice back in my days, who had respect for their elders and didn't worry, they just carried on like normal mice do.

At what point does it even make sense to speak of anxiety, which is defined as worrying about things, when we are about 400 layers past the point where people just invented "generalized anxiety", then made it all about certain non-specific symptoms that may or may not have anything to do with thoughts and beliefs?

There is the old belief that this non-coding DNA was just useless junk, but damn does medicine have this weird obsession with doing that, with keeping old nonsense that has nothing to do with the studied phenomenon just because they can't let go of it. They just carry those junk beliefs around instead.

 

[FMMM1]

Did this turn up via GWAS, whole genome sequencing---?

Tagging @JonathanEdwards in case he missed this (unlikely!).

EDIT - found by deleting genes (CRISPR) and looking at effect. Reminds me of an OMF talk where they found a mouse overgrooming (self harm) when they edited a gene (using CRISPR I guess).
CRISPR is really cheap & accessible - students in some secondary schools get to use it!

 

[FMMM1]

Mice these days, always worried and stressed about their marbles. Not like the mice back in my days, who had respect for their elders and didn't worry, they just carried on like normal mice do.

At what point does it even make sense to speak of anxiety, which is defined as worrying about things, when we are about 400 layers past the point where people just invented "generalized anxiety", then made it all about certain non-specific symptoms that may or may not have anything to do with thoughts and beliefs?

There is the old belief that this non-coding DNA was just useless junk, but damn does medicine have this weird obsession with doing that, with keeping old nonsense that has nothing to do with the studied phenomenon just because they can't let go of it. They just carry those junk beliefs around instead.

Yea sort of asks questions of those who claim that this (anxiety) is controlled by will power, positive thinking -- - some have it and some don't (i.e. will power, positive thinking -- -). Also, reminds me of Wallitt - "effort preference"!

 

[Hutan]

I tried to pick my way through the abstract. I'm not sure about their mice work - there seemed to possibly be some post-hoc subsetting of samples (male/female mice; different parts of the brain) in order to find a result. I think this might be a takeaway point, from the article:

He said: “We already know that 95% of the genetic differences associated with disease are found outside of protein coding genes.
“This part of the genome, known as the “non-coding genome” has not been well explored because we previously lacked the tools to do so.
“We also know that the non-coding genome contains information in the form of gene switches that tell genes where and when to be turned on.

Also worth noting

highly significant effect on BDNF-antisense (BDNF-AS) gene expression and splicing

anti-sense?

Antisense RNA is a single stranded RNA that is complementary to a protein coding messenger RNA with which it hybridizes, and thereby blocks its translation into protein.

 

[Creekside]

I can see a possible use for this line of study: improving mousetraps. Would traps be more effective if designed for specific mouse disorders? Mice with anxiety might be attracted by greasy bait, while depressed ones might favour blue traps. If nothing else, each psychologist working on mice means one less screwing up human lives.