Expressive

rs10784502 (HMGA2): Intracranial Volume Variant

Key takeaways

  • rs10784502 lies within the HMGA2 gene at chromosomal region 12q14.3
  • It is linked to intracranial volume at genome-wide significance (P = 1.12 × 10^-¹²) in ~15,782 people
  • Intracranial volume is estimated to be 78-84% heritable based on twin and pedigree studies
  • The alternative allele is associated with reduced HMGA2 expression in cultured fibroblasts
  • All genetic association evidence comes from European ancestry populations

Key takeaways

  • rs10784502 lies within the HMGA2 gene at chromosomal region 12q14.3
  • It is linked to intracranial volume - the total space inside the skull - at genome-wide significance (P = 1.12 × 10^-¹²) in ~15,782 people
  • Intracranial volume is estimated to be 78-84% heritable based on twin and pedigree studies
  • The alternative allele at this locus is associated with reduced expression of both HMGA2 and a neighboring gene in cultured fibroblasts
  • All genetic association evidence comes from European ancestry populations

What the research says rs10784502, located within HMGA2 (chromosome 12q14.3), was associated with intracranial volume - the measured space enclosed by the skull - at genome-wide significance in a meta-analysis of 17 European ancestry cohorts (N = 15,782, P = 1.12 × 10^-¹²). In the same investigation, intracranial volume was estimated to be between 78% and 84% heritable in twin and extended-pedigree samples, indicating that genetics accounts for a substantial share of variation in this trait. The same study separately identified a genome-wide significant association for hippocampal volume at a different nearby locus (rs7294919, 12q24.22, N = 21,151, P = 6.70 × 10^-¹^6), linked to expression of the TESC gene in brain tissue - evidence that neighboring loci can affect distinct brain structures through different molecular pathways.

Reported associations

  • Intracranial volume: Genome-wide significant association at the HMGA2 locus (12q14.3; P = 1.12 × 10^-¹², N = 15,782), identified by meta-analysis of 17 European ancestry cohorts with replication attempted in the combined CHARGE Consortium and 3C replication cohort (N = 10,779) and additional independent samples

Evidence quality The intracranial volume association (P = 1.12 × 10^-¹²) substantially exceeds the conventional genome-wide significance threshold (P = 5 × 10^-8). Discovery was performed across 17 European ancestry cohorts; replication was conducted in silico in the CHARGE Consortium and 3C replication cohort (N = 10,779) as well as in two smaller independent European ancestry cohorts, with custom genotyping in two additional samples. Analyses for intracranial and total brain volume were restricted to healthy subjects, excluding participants ascertained for neuropsychiatric disorders. All available samples are of European ancestry, and generalizability to other populations is unknown. No conflicting reports for rs10784502 appear in the provided studies. The available eQTL evidence (tissue-specific gene expression data) comes exclusively from cultured fibroblasts in GTEx v11; expression effects in brain tissue have not been established in the provided data, so the mechanistic link between this eQTL signal and intracranial volume remains to be characterized.

Tissue-specific expression effects

  • HMGA2: The alternative allele is associated with reduced expression of this gene in cultured fibroblasts GTEx Portal
  • ENSG00000256083: The alternative allele is also associated with reduced expression of this neighboring gene in cultured fibroblasts GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.

Lifestyle context

Concrete actions anchored to the cited research. We do not prescribe, we describe.

Screening

  • Systolic blood pressure Moderate

    C allele at rs10784502 associates with modestly elevated systolic blood pressure in population studies

    Annual screening; more frequent if cardiovascular risk factors present

Frequently asked questions

What is rs10784502 and what gene is it in?

rs10784502 is a common genetic variant located within the HMGA2 gene at chromosomal region 12q14.3 on chromosome 12.

What trait is rs10784502 associated with?

This variant is associated with intracranial volume - the total space enclosed by the skull. The association reached genome-wide significance in a meta-analysis of nearly 16,000 individuals of European ancestry.

How heritable is intracranial volume?

Twin and pedigree studies estimate intracranial volume is between 78% and 84% heritable, meaning most variation in this trait is attributable to genetic differences rather than environment.

Does rs10784502 affect gene expression?

Yes. GTEx data show the alternative allele at rs10784502 is associated with reduced expression of HMGA2 and a neighboring gene (ENSG00000256083) in cultured fibroblasts. Expression effects in brain tissue have not been reported in the available data.

Is rs10784502 related to hippocampal volume or brain disease?

No. This variant was specifically associated with intracranial volume, not hippocampal volume. A distinct nearby variant, rs7294919, was associated with hippocampal volume in the same study. Intracranial volume is a structural brain measure and is not itself a direct marker of any specific disease.