Expressive

rs12144094 (PHGDH): Height variant and gene expression

Key takeaways

  • rs12144094 sits in the PHGDH region and was identified in a 253,288-person GWAS as one of 697 variants linked to adult height.
  • The 697 height-associated variants from that study together explain roughly one-fifth of the heritability for adult height.
  • This variant is associated with reduced ZNF697 expression in six tissues, including skeletal muscle and aortic artery.
  • It is also linked to increased PHGDH expression in testis, where PHGDH encodes an enzyme central to serine biosynthesis.
  • No variant-specific effect size is available and no lifestyle recommendations follow from current evidence.

Key takeaways

  • rs12144094 sits in the PHGDH (phosphoglycerate dehydrogenase) region and was identified in a GWAS of 253,288 individuals as one of 697 variants linked to adult height.
  • Those 697 variants together explain roughly one-fifth of the heritability for adult height in people of European ancestry.
  • This variant is associated with reduced expression of the nearby ZNF697 gene across six tissue types, including skeletal muscle and aortic artery tissue.
  • It is also linked to increased expression of PHGDH, an enzyme involved in serine biosynthesis, in testis tissue.
  • No variant-specific effect size is available in the provided materials, and no lifestyle recommendations follow from current evidence.

What the research says A GWAS meta-analysis of 253,288 individuals across 79 studies identified 697 variants at genome-wide significance (a strict statistical cutoff, p < 5 x 10-8) linked to adult height, collectively explaining approximately one-fifth of heritability. rs12144094 sits in the PHGDH region, where PHGDH (phosphoglycerate dehydrogenase) encodes the first enzyme in the serine biosynthesis pathway. Gene expression data from GTEx v11 (953 donors) show that the alternate allele is associated with reduced ZNF697 expression in six tissues and increased PHGDH and ENSG00000296692 expression in testis GTEx Portal.

Reported associations

  • Adult height: Identified among 697 genome-wide significant variants in a meta-analysis of 253,288 European-ancestry individuals; the full set of 697 variants explained approximately one-fifth of phenotypic variance for height.
  • ZNF697 expression (reduced): The alternate allele is associated with lower ZNF697 expression in esophagus mucosa, spleen, cultured fibroblasts, aortic artery, skeletal muscle, and tibial artery GTEx Portal.
  • PHGDH expression (increased): The alternate allele is linked to higher PHGDH expression in testis tissue GTEx Portal.
  • ENSG00000296692 expression (increased): The alternate allele is linked to higher expression of a neighboring unannotated gene (ENSG00000296692) in testis tissue GTEx Portal.

Evidence quality The height association is derived from a meta-analysis of 79 studies totaling 253,288 individuals of European ancestry, with effect sizes replicated in 80,067 additional individuals via Metabochip genotyping (greater than 99% directional consistency). The 697 significant variants together explained approximately 20% of phenotypic variance for height; broader sets of up to 9,500 SNPs captured approximately 29% of variance. No variant-specific effect size for rs12144094 is provided in the available study text. The GTEx eQTL (expression quantitative trait locus) associations are from GTEx v11 (953 donors), reported at FDR less than 0.05; these represent statistical associations between genotype and gene expression, and their functional or clinical significance is not established in the provided materials. No conflicting findings are present across the provided sources.

Tissue-specific expression effects

  • ZNF697: The alternate allele is associated with reduced expression in esophagus mucosa, spleen, cultured fibroblasts, aortic artery, skeletal muscle, and tibial artery GTEx Portal.
  • PHGDH: The alternate allele is associated with increased expression in testis GTEx Portal.
  • ENSG00000296692: The alternate allele is associated with increased expression in testis GTEx Portal.

Lifestyle considerations No lifestyle considerations on file for this variant.

Frequently asked questions

What is the PHGDH gene?

PHGDH encodes phosphoglycerate dehydrogenase, an enzyme that catalyzes the first step in the serine biosynthesis pathway. Serine is an amino acid involved in protein synthesis and a range of cellular processes.

Is rs12144094 linked to adult height?

rs12144094 is located in the PHGDH region and was identified among 697 genome-wide significant variants in a GWAS of 253,288 individuals. Together those variants explain about one-fifth of the heritability for adult height in people of European ancestry.

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

An eQTL (expression quantitative trait locus) is a genetic variant that affects how actively a nearby gene is expressed in cells. GTEx data show that rs12144094 reduces ZNF697 expression in multiple tissues and increases PHGDH expression in testis, suggesting this variant may exert biological effects through changes in gene activity rather than changes to a protein sequence.

What does it mean that this variant reduces ZNF697 expression in muscle?

GTEx data show a statistical association between the alternate allele and lower ZNF697 gene activity in skeletal muscle and five other tissues. This is a molecular observation; the physiological consequences for muscle function or health are not established in the provided evidence.

How strong is the evidence for the height association?

The association comes from a large meta-analysis of 253,288 individuals replicated in over 80,000 more people, with greater than 99% of variants showing directional consistency. However, no effect size specific to rs12144094 alone is available in the provided materials, and the 697 significant variants collectively explain only about 20% of height variance.