Expressive

rs10804178 (UNC80): Height and Brain Expression

Key takeaways

  • One of 12,111 common variants linked to adult height in the largest height GWAS to date, spanning 5.4 million participants
  • The alternate allele increases RPE gene expression in the brain's frontal cortex and five other tissues
  • The same allele reduces KANSL1L and a second uncharacterized gene's expression in the pituitary gland
  • These height variants together explain 40-45% of height variation in European-ancestry populations, but only 10-24% in other ancestry groups
  • The lower prediction accuracy in non-European populations reflects differences in genetic structure, not different causal biology

Key takeaways

  • One of 12,111 common variants linked to adult height in the largest height GWAS to date, spanning 5.4 million participants
  • The alternate allele increases RPE gene expression in the brain's frontal cortex and five other tissues
  • The same allele reduces KANSL1L and a second uncharacterized gene's expression in the pituitary gland
  • These height variants together explain 40-45% of height variation in European-ancestry populations, but only 10-24% in other ancestry groups
  • The lower prediction accuracy in non-European populations reflects differences in genetic structure, not different causal biology

What the research says rs10804178, near the UNC80 gene, was identified among 12,111 independent SNPs significantly associated with adult height in a genome-wide association study (GWAS) of 5.4 million individuals across 281 cohorts, with associated regions covering roughly 21% of the genome across 7,209 non-overlapping segments. These SNPs collectively account for approximately 40% of height variance in European-ancestry populations (rising to 45% using the full HapMap 3 panel of common genetic variants), but only 10-24% in populations of other ancestries - a gap attributed to differences in linkage disequilibrium (the tendency for nearby genetic variants to be inherited together across a population) rather than distinct causal variants. In addition, GTEx tissue expression data show the alternate allele at this locus is associated with increased expression of the RPE gene across six tissues and reduced expression of KANSL1L and an uncharacterized gene in the pituitary gland GTEx Portal.

Reported associations

  • Adult height: Identified as one of 12,111 significantly associated common SNPs in a meta-analysis of 5.4 million participants; these SNPs together explain approximately 40-45% of height variance in European-ancestry populations
  • RPE gene expression: Alternate allele associated with increased expression across six tissues; strongest signal in brain frontal cortex BA9 (effect size beta +0.19, p=2.3e-8) GTEx Portal
  • KANSL1L gene expression (pituitary): Alternate allele associated with reduced expression in the pituitary gland (effect size beta -0.17, p=1.4e-5) GTEx Portal
  • ENSG00000272807 expression (pituitary): Alternate allele associated with reduced expression of this uncharacterized gene in the pituitary gland (effect size beta -0.17, p=3.2e-5) GTEx Portal

Evidence quality The height association for this locus rests on a sample of 5.4 million individuals from 281 studies - among the largest discovery cohorts ever assembled for a single trait. The 12,111 significant SNPs cluster in 7,209 non-overlapping genomic segments covering roughly 21% of the genome, collectively accounting for nearly all common-variant heritability for height. Prediction accuracy reaches approximately 40% of variance explained in European-ancestry populations using the significant SNPs alone, and 45% with the full HapMap 3 panel. Prediction accuracy is substantially reduced in non-European ancestries (10-20% for significant SNPs; 14-24% for the full panel), attributed to differences in linkage disequilibrium and allele frequency rather than different causal variants. No conflicting evidence for the height association is present in the provided material. The GTEx eQTL signals (expression quantitative trait loci: statistical associations between a genetic variant and the expression level of a nearby gene) are based on 953 donors under false discovery rate (FDR less than 0.05) analysis; these expression effects represent potential molecular mechanisms and do not by themselves indicate clinical outcomes GTEx Portal.

Tissue-specific expression effects

  • RPE: Increased expression with the alternate allele in brain frontal cortex (BA9), adrenal gland, skeletal muscle, sun-exposed skin, breast mammary tissue, and tibial nerve GTEx Portal
  • KANSL1L: Reduced expression in the pituitary gland with the alternate allele GTEx Portal
  • ENSG00000272807: Reduced expression in the pituitary gland with the alternate allele GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.

Frequently asked questions

What is rs10804178?

rs10804178 is a common genetic variant located near the UNC80 gene. It is one of 12,111 SNPs found to be significantly associated with adult height in the largest height genome-wide association study to date, covering 5.4 million participants, and it also influences gene expression in several tissues.

Is rs10804178 linked to height?

Yes. This variant was identified among 12,111 common SNPs significantly associated with adult height in a genome-wide study of 5.4 million people across 281 cohorts. Together, these variants explain about 40-45% of the genetic variation in height in people of European ancestry.

What tissues does rs10804178 affect?

Based on GTEx gene expression data, the alternate allele of rs10804178 is linked to increased activity of the RPE gene in the brain's frontal cortex, adrenal gland, skeletal muscle, skin, breast tissue, and tibial nerve. It also shows reduced activity of the KANSL1L gene and a second uncharacterized gene in the pituitary gland.

Why is genetic ancestry relevant to height prediction for rs10804178?

The height study found that the set of common variants including rs10804178 explains 40-45% of height variation in people of European ancestry but only about 10-24% in other ancestry groups. Researchers attribute this difference to variation in how nearby genetic variants are inherited together (linkage disequilibrium) across populations, not to different causal genes.

What is an eQTL and why does it matter for this variant?

An eQTL (expression quantitative trait locus) is a genetic variant statistically associated with changes in how much a nearby gene is expressed in a tissue. For rs10804178, GTEx data show it acts as an eQTL for RPE, KANSL1L, and a third gene across multiple tissues, providing a potential molecular mechanism, though expression effects alone do not establish clinical outcomes.