A Genome-Wide Association Study of Northwestern Europeans Involves the C-type Natriuretic Peptide Signaling Pathway in the Etiology of Human Height Variation

Hum Mol Genet. 2009 Sep 15;18(18):3516-24. doi: 10.1093/hmg/ddp296. Epub 2009 Jul 1.

Abstract

Northwestern Europeans are among the tallest of human populations. The increase in body height in these people appears to have reached a plateau, suggesting the ubiquitous presence of an optimal environment in which genetic factors may have exerted a particularly strong influence on human growth. Therefore, we performed a genome-wide association study (GWAS) of body height using 2.2 million markers in 10 074 individuals from three Dutch and one German population-based cohorts. Upon genotyping, the 12 most significantly height-associated single nucleotide polymorphisms (SNPs) from this GWAS in 6912 additional individuals of Dutch and Swedish origin, a genetic variant (rs6717918) on chromosome 2q37.1 was found to be associated with height at a genome-wide significance level (P(combined) = 3.4 x 10(-9)). Notably, a second SNP (rs6718438) located approximately 450 bp away and in strong LD (r(2) = 0.77) with rs6717918 was previously found to be suggestive of a height association in 29 820 individuals of mainly northwestern European ancestry, and the over-expression of a nearby natriuretic peptide precursor type C (NPPC) gene, has been associated with overgrowth and skeletal anomalies. We also found a SNP (rs10472828) located on 5p14 near the natriuretic peptide receptor 3 (NPR3) gene, encoding a receptor of the NPPC ligand, to be associated with body height (P(combined) = 2.1 x 10(-7)). Taken together, these results suggest that variation in the C-type natriuretic peptide signaling pathway, involving the NPPC and NPR3 genes, plays an important role in determining human body height.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Body Height*
  • European Continental Ancestry Group / genetics*
  • Female
  • Gene Expression Regulation
  • Genome, Human*
  • Genome-Wide Association Study
  • Germany
  • Humans
  • Male
  • Middle Aged
  • Natriuretic Peptide, C-Type / genetics*
  • Netherlands
  • Polymorphism, Single Nucleotide
  • Protein Precursors / genetics*
  • Receptors, Atrial Natriuretic Factor / genetics*
  • Signal Transduction*

Substances

  • Protein Precursors
  • Natriuretic Peptide, C-Type
  • Receptors, Atrial Natriuretic Factor
  • atrial natriuretic factor receptor C