A genome-wide association study of northwestern Europeans involves the C-type natriuretic peptide signaling pathway in the etiology of human height variation.

Karol Estrada, Michael Krawczak, Stefan Schreiber, Kate van Duijn, Lisette Stolk, Joyce B J van Meurs, Fan Liu, Brenda W J H Penninx, Jan H Smit, Nicole Vogelzangs, Jouke Jan Hottenga, Gonneke Willemsen, Eco J C de Geus, Mattias Lorentzon, Huberta von Eller-Eberstein, Paul Lips, Natascha Schoor, Victor Pop, Jules de Keijzer, Albert Hofman, Yurii S Aulchenko, Ben A Oostra, Claes Ohlsson, Dorret I Boomsma, Andre G Uitterlinden, Cornelia M van Duijn, Fernando Rivadeneira, Manfred Kayser
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Human molecular genetics
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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.