Human Molecular Genetics Advance Access published online on October 24, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn350
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Common variants in the JAZF1 gene associated with height identified by linkage and genome-wide association analysis
1 Department of Genetics and Pathology, Rudbeck laboratory, Uppsala University, SE-751 85, Uppsala, Sweden 2 Institute of Genetic Medicine, European Academy, Viale Druso 1, I-39100 Bolzano, Italy 3 MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, EH4 2XU, UK 4 Public Health Sciences, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG, Scotland 5 Institute of Cytology and Genetics, Siberian Division of Russian Academy of Sciences, 630090 Novosibirsk, Russia 6 Genetic Epidemiology Unit, Department of Epidemiology and Clinical Genetics, Erasmus University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, he Netherlands 7 Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Edinburgh EH4 2XU, UK 8 The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Roslin BioCentre, Midlothian, EH25 9PS, Scotland 9 Institute of Evolutionary Biology, University of Edinburgh, West Mains Road, Edinburgh, EH9 3JT, Scotland 10 Andrija Stampar School of Public Health, University of Zagreb Medical School, Rockefellerova 4, 10000 Zagreb, Croatia 11 Genetic Laboratory, Department of Internal Medicine, Erasmus University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, he Netherlands 12 Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstaedter Landstr. 1, D-85764 Neuherberg, Germany 13 Croatian Centre for Global Health, University of Split Medical School, Soltanska 2, 21000 Split, Croatia 14 Institute for Clinical Medical Research, University Hospital "Sestre Milosrdnice", Zagreb, Croatia 15 Department of Neurology, Central Hospital, Bolzano, Italy
* All correspondence concerning the manuscript should be addressed to: Dr Ulf Gyllensten Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, S-571 85, Uppsala, Sweden. Phone: 46-18-4714909 Email: ulf.gyllensten{at}genpat.uu.se Fax: 46-18-4714931
Received August 27, 2008; Revised October 16, 2008; Accepted October 16, 2008
Genes for height has gained interest for decades, but only recently have candidate genes started to be identified. We have performed linkage analysis and genome-wide association for height in approximately 4,000 individuals from five European populations. A total of 5 chromosomal regions showed suggestive linkage and in one of these regions, two SNPs (rs849140 and rs1635852) were associated with height (nominal p=7.0 x 10–8 and p=9.6 x 10–7 respectively). In total, five SNPs across the genome showed an association with height that reached the threshold of genome-wide significance (nominal p<1.6 x 10–7). The association with height was replicated for two SNPs (rs1635852 and rs849140) using three independent studies (N=31,077, N=1,268 and N=5,746) with overall meta p-values of 9.4x10–10 and 5.3x10–8. These SNPs are located in the JAZF1 gene, which has recently been associated with type II diabetes, prostate and endometrial cancer. JAZF1 is a transcriptional repressor of NR2C2, which results in low IGF1 serum concentrations, perinatal and early postnatal hypoglycaemia and growth retardation when knocked-out in mice. Both the linkage and association analyses independently identified the JAZF1 region affecting human height. We have demonstrated, through replication in additional independent populations, the consistency of the effect of the JAZF1 SNPs on height. Since this gene also has a key function in the metabolism of growth, JAZF1 represents one of the strongest candidates influencing human height so far identified.
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