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Human Molecular Genetics Advance Access originally published online on July 1, 2009
Human Molecular Genetics 2009 18(18):3516-3524; doi:10.1093/hmg/ddp296
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© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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

Karol Estrada1, Michael Krawczak5,7, Stefan Schreiber6,7, Kate van Duijn2, Lisette Stolk1,3, Joyce B.J. van Meurs1, Fan Liu2, Brenda W.J.H. Penninx8, Jan H. Smit8, Nicole Vogelzangs8, Jouke Jan Hottenga9, Gonneke Willemsen9, Eco J.C. de Geus9, Mattias Lorentzon11, Huberta von Eller-Eberstein6, Paul Lips10, Natascha Schoor10, Victor Pop12, Jules de Keijzer12, Albert Hofman3, Yurii S. Aulchenko4,13, Ben A. Oostra4, Claes Ohlsson11, Dorret I. Boomsma9, Andre G. Uitterlinden1,3, Cornelia M. van Duijn4, Fernando Rivadeneira1,3 and Manfred Kayser2,*

1 Genetics Laboratory, Department of Internal Medicine, 2 Department of Forensic Molecular Biology, 3 Department of Epidemiology and 4 Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands, 5 Institute of Medical Informatics and Statistics and 6 Institute of Clinical Molecular Biology, Christian-Albrechts University Kiel, Kiel, Germany, 7 PopGen Biobank, University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany, 8 EMGO Institute/Department of Psychiatry, 9 Department of Biological Psychology and 10 Department of Internal Medicine, Endocrine Section, and EMGO Institute, Free University Medical Center Amsterdam, Amsterdam, The Netherlands, 11 Center for Bone Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden, 12 Department of Clinical Health Psychology, University of Tilburg, Tilburg, The Netherlands and 13 Institute of Cytology and Genetics, SDRAS, Novosibirsk 630090, Russia

* To whom correspondence should be addressed at: Department of Forensic Molecular Biology, Erasmus University Medical Center Rotterdam, PO Box 2040, Rotterdam, 3000 CA, The Netherlands. Tel: +31 107038073; Fax: +31 107044575; Email: m.kayser{at}erasmusmc.nl

Received March 31, 2009; Accepted June 23, 2009

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 (Pcombined = 3.4 x 10–9). Notably, a second SNP (rs6718438) located ~450 bp away and in strong LD (r2 = 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 (Pcombined = 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.


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