Huntington's disease itself comes from one well-known cause, a CAG-repeat expansion in HTT — this page is about something narrower: one variant found to shift the age symptoms begin, and only in the same Venezuelan family cluster whose DNA first mapped HTT itself, in 1983.
Huntington's disease is caused by a single, well-established mutation — an expanded CAG repeat in the HTT gene, first mapped in 1983 and not something this page covers, since this site holds no variant for it. What this page holds is different: one locus found to modify when symptoms begin in someone who already carries that expansion, and it was found in a very specific place.
The Venezuelan family cluster around Lake Maracaibo is the population whose DNA samples, collected in the 1980s by Nancy Wexler, were used to map HTT itself. Chao et al. 2018 returned to 549 members of that same cluster and asked a different question: among people who all carry the expansion, why do some develop symptoms years earlier than others?
Age at onset already tracks the length of the CAG repeat itself — a longer repeat generally means earlier onset — so the study corrected for repeat length and searched for anything else moving the remaining variation. One signal reached genome-wide significance: rs12668183 on chromosome 7, where each copy of the minor allele was associated with onset 2.8 years earlier (p=2×10⁻⁸).
The same analysis was run on European Huntington's disease subjects, and rs12668183 showed no effect there at all — the authors checked this directly rather than assuming a Venezuelan finding would generalize. That makes it a genuine population-specific modifier, not a general Huntington's disease finding that merely happened to be discovered in one cohort first.
One naming note worth being precise about: this site's own catalogue, like the GWAS Catalog, maps rs12668183 to CRPPA by nearest-gene distance. The paper's own functional case, though, points to the neighboring gene SOSTDC1 — the associated SNPs are linked to reduced SOSTDC1 expression in independent tissue data, and the authors' working hypothesis is that lower SOSTDC1 (a bone-morphogenetic-protein antagonist) contributes to the earlier onset. The nearest gene and the gene the evidence actually implicates are not the same one here, and the page says so rather than picking silently.
2026-09-14 · Kay C, et al. Neuron. 2026. DOI:10.1016/j.neuron.2026.08.010
A team at the University of British Columbia's Centre for Molecular Medicine and Therapeutics, led by Dr. Michael Hayden, found that some Huntington's disease patients carry a variant that removes a normally stabilizing interruption inside the HTT gene's CAG repeat tract -- the same repeat whose overall length is the disease's core known driver. Carriers of this loss-of-interruption variant showed roughly five times more somatic expansion of the repeat inside their neurons than patients without it, fewer surviving neurons, and earlier loss of the specific nerve cells Huntington's targets -- translating into symptom onset 10 to 12 years earlier. This is a mechanistically distinct finding from the variant already catalogued on this page (a CRPPA locus identified through a genome-wide modifier scan): that earlier finding is a common variant elsewhere in the genome that shifts age at onset modestly, while this new finding is a structural change inside the repeat tract itself, with a much larger and more direct effect on how fast the repeat grows inside neurons over a lifetime. This specific structural variant does not yet have a published rsID-level GWAS Catalog record, so no new variant page was added.
2026-07-28 · Kerrebijn I, et al., Nature Medicine 2026, PMID:42521817
The genetic architecture of fibromyalgia across 2.5 million individuals
Fibromyalgia is a common, debilitating chronic pain syndrome whose cause has been poorly understood. This multi-ancestry meta-analysis covers 2,563,755 people from 11 cohorts — 54,629 with fibromyalgia and 2,509,126 without — and finds 26 risk loci. The strongest association is a coding variant in HTT, the gene that causes Huntington's disease; gene prioritisation also points to the HTT regulator GPR52 and to genes with neural roles (DCC, DRD2/NCAM1, MDGA2, CELF4). Heritability was enriched exclusively in brain tissues and neural cell types, and fibromyalgia correlated genetically above 0.7 with low back pain, post-traumatic stress disorder and irritable bowel syndrome. Despite the large difference in prevalence between the sexes, the genetic architecture was nearly identical in males and females. The authors read this as genetic evidence that fibromyalgia is a disorder of the central nervous system. Three of the study's positions are on this site under other traits: rs9862795 (near CAMKV), rs809955 (MAML3) and rs11167957 (PPP2R2B). PMID:42521817.
Huntington's disease is diagnosed by genetic testing for the HTT CAG-repeat expansion, not by this variant. rs12668183 has no bearing on whether someone develops Huntington's disease — only, in one studied population, on when symptoms began among people who already carry the expansion.
The effect size (2.8 years per copy) and its population-specificity come from 549 people in one family cluster. It has not been shown to apply outside that population, and a single study — even one this directly targeted — is not the same as a validated clinical modifier.
What a 23andMe/AncestryDNA export or raw VCF can and can't tell you about Huntington's Disease (Age at Onset) comes down to these specific, well-studied positions — not a diagnosis.
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Huntington's Disease (Age at Onset). MyGeneLog™. https://www.mygenelog.com/conditions/huntington-disease-age-at-onset
Huntington's disease is caused by an expanded CAG repeat in the HTT gene, first mapped in 1983. This page is not about that mutation — it covers a separate variant that modifies age at onset, not the cause itself.
No. It has no bearing on whether someone develops Huntington's disease — only, in one studied Venezuelan family cluster, on when symptoms began among people who already carry the causal CAG expansion.
The Venezuelan family cluster near Lake Maracaibo is the same population whose DNA first mapped the HTT gene itself in 1983. Researchers returned to 549 members of that cluster in 2018 and found this age-at-onset modifier — then checked it in European patients and found no effect there, confirming it is population-specific.
By nearest-gene distance, yes — that is how this site and the GWAS Catalog map it. But the paper's own functional evidence points to the neighboring gene SOSTDC1, whose reduced expression is the authors' working explanation for the earlier onset.
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