Genetics: Chromosome 4, HTT

[Hutan]

From a discussion on the Eccentric Medium Spiny Neurons thread:
DecodeME identified HTT as of interest.

HTT and spiny neurons seems maybe worthy of more investigation, they seem very interrelated. It’s not a gene I think we spent much time on but was one of the DecodeME candidates even if a bit below the threshold.

LocusZoom for HTT.

Agree, thanks for pointing this out!

To give a bit more background: HTT stands for Huntingtin, the gene behind the Huntington disease.

HTT is important for axonal transport and helps in regulating the expression of survival factors like BDNF (Brain-Derived Neurotrophic Factor). Medium spinal nerves (I suppose this includes the eccentric ones) are particularly dependent on HTT and thus the first to be affected in Huntington disease.

Despite the widespread expression of huntingtin, HD has long been considered primarily as a disease of the striatum. It is characterized by selective vulnerability with dysfunction followed by death of the medium size spiny neuron.

Huntington's Disease and the Striatal Medium Spiny Neuron: Cell-Autonomous and Non-Cell-Autonomous Mechanisms of Disease - ScienceDirect

 

[Hutan]

 

[Hutan]

It was also noted that it came up in a fibromyalgia GWAS

HTT was flagged in the fibromyalgia GWAS study preprint: "The strongest association was with a coding variant in HTT…"

V

Thread 'The genetic architecture of fibromyalgia across 2.5 million individuals, 2025, Kerrebijnet al.'

Sep 26, 2025

Abstract​

Fibromyalgia is a common and debilitating chronic pain syndrome of poorly understood etiology. Here, we conduct a multi-ancestry genome-wide association study meta-analysis across 2,563,755 individuals (54,629 cases and 2,509,126 controls) from 11 cohorts, identifying the first 26 risk loci for fibromyalgia. The strongest association was with a coding variant in HTT , the causal gene for Huntington's disease. Gene prioritization implicated the HTT regulator GPR52 , as well as diverse genes with neural roles, including CAMKV , DCC ...

• voner
• arhgap dcc drd2 fibromyalgia genetics gwas rabgap1l rho gtpase
• Replies: 25
• Forum: 'Conditions related to ME/CFS' news and research

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We found a second association with a possible HD link: rs6657341-A (OR = 0.961, p = 7.1 × 10-9 ), an intronic variant in RABGAP1L, ~150 kilobases upstream of its second-nearest gene GPR52. RABGAP1L regulates RAB proteins, which direct intracellular trafficking, but has no clear link to fibromyalgia. Conversely, GPR52 is a brain-specific orphan G-protein coupled receptor being investigated as a drug target for HD as it regulates HTT levels.

RABGAP1L was a hit in DecodeME - thread here
GPR52 was also a hit in DecodeME

 

[hotblack]

Some more background info:

The striatum refers to a small group of contiguous subcortical structures: the caudate, putamen, and nucleus accumbens.

The striatum is one of the principal components of the basal ganglia, a group of nuclei that have a variety of functions but are best known for their role in facilitating voluntary movement.

Source: https://neuroscientificallychallenged.com/posts/know-your-brain-striatum