Human Molecular Genetics Advance Access originally published online on October 24, 2008
Human Molecular Genetics 2009 18(2):373-380; 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 Rudbeck Laboratory, Department of Genetics and Pathology, 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, UK 5 Siberian Division of Russian Academy of Sciences, Institute of Cytology and Genetics, 630090 Novosibirsk, Russia 6 Genetic Epidemiology Unit, Department of Epidemiology and Clinical Genetics 7 Genetic Laboratory, Department of Internal Medicine, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands 8 Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, MRC Human Genetics Unit, University of Edinburgh, Edinburgh EH4 2XU, UK 9 The Roslin Institute, Royal (Dick) School of Veterinary Studies, Roslin BioCentre, University of Edinburgh, Midlothian EH25 9PS, UK 10 Institute of Evolutionary Biology, University of Edinburgh, West Mains Road, Edinburgh EH9 3JT, UK 11 Andrija Stampar School of Public Health, University of Zagreb Medical School, Rockefellerova 4, 10000 Zagreb, Croatia 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
* To whom correspondence should be addressed. Tel: +46 184714909; Fax: +46 184714931; Email: ulf.gyllensten{at}genpat.uu.se
Received August 27, 2008; Accepted October 16, 2008
Genes for height have 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 4000 individuals from five European populations. A total of five 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=1268 and n = 5746) with overall meta P-values of 9.4 x 10–10 and 5.3 x 10–8. 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 hypoglycemia 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 identified so far.
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