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Human Molecular Genetics Advance Access published online on July 1, 2009
Human Molecular Genetics, 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 CNP signaling pathway in the etiology of human height variation

Karol Estrada1, Michael Krawczak2,3, Stefan Schreiber3,4, Kate van Duijn5, Lisette Stolk1,6, Joyce B.J. van Meurs1, Fan Liu5, Brenda W.J.H. Penninx7, Jan H. Smit7, Nicole Vogelzangs7, Jouke Jan Hottenga8, Gonneke Willemsen8, Eco J.C. de Geus8, Mattias Lorentzon9, Huberta von Eller-Eberstein4, Paul Lips10, Natascha Schoor10, Victor Pop11, Jules de Keijzer11, Albert Hofman6, Yurii S. Aulchenko12,13, Ben A. Oostra12, Claes Ohlsson9, Dorret I. Boomsma8, Andre G. Uitterlinden1,6, Cornelia M. van Duijn12, Fernando Rivadeneira1,6 and Manfred Kayser5,*

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

* Corresponding author: Prof. Dr. Manfred Kayser, Department of Forensic Molecular Biology, Erasmus University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, The Netherlands, Tel: ++31-10-7038073, Fax: ++31-10-7044575, Email: m.kayser{at}erasmusmc.nl

Received March 31, 2009; Revised June 23, 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 (CNP) signaling pathway, involving the NPPC and NPR3 genes, plays an important role in determining human body height.


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