Obesity, a common multifactorial disorder, is a major risk factor for type 2 diabetes, hypertension and coronary heart disease1 (CHD). According to the definition of the World Health Organization (WHO), approximately 6-10% of the population in Westernized countries are considered obese2. Epidemiological studies have shown that 30-70% of the variation in body weight may be attributable to genetic factors. To date, two genome-wide scans using different obesity-related quantitative traits have provided candidate regions for obesity3,4. We have undertaken a genome-wide scan in affected sibpairs to identify chromosomal regions linked to obesity in a collection of French families. Model-free multipoint linkage analyses revealed evidence for linkage to a region on chromosome 10p (MLS=4.85). Two further loci on chromosomes 5cen–q and 2p showed suggestive evidence for linkage of serum leptin levels in a genome-wide context. The peak on chromosome 2 coincided with the region containing the gene (POMC) encoding pro-opiomelanocortin, a locus previously linked to leptin levels and fat mass in a Mexican-American population3 and shown to be mutated in obese humans5. Our results suggest that there is a major gene on chromosome 10p implicated in the development of human obesity, and the existence of two further loci influencing leptin levels.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Frayn, K.N. & Coppack, S.W. Insulin resistance, adipose tissue and coronary heart disease. Clin. Sci. Colch. 82, 1–8 (1992).
de Onis, M. & Habicht, J.P. Anthropometric reference data for international use: recommendations from a World Health Organisation Expert Committee. Am. J. Clin. Nutr. 64, 650– 658 (1996).
Comuzzie, A.G. et al. A major quantitative trait locus determining serum leptin levels and fat mass is located on human chromosome 2. Nature Genet. 15, 273–276 (1997).
Norman, R.A. et al. Autosomal genomic scan for loci linked to obesity and energy metabolism in Pima Indians. Am. J. Hum. Genet. 62, 659–668 (1998).
Krude, K. et al. Severe early onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nature Genet. 19, 155–157 (1998).
Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425– 434 (1994).
Chen, H. et al. Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 84, 491–495 (1996).
Naggert, J.K. et al. Hyperproinsulinemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity. Nature Genet. 10, 153–142 (1995).
Noben-Trauth, K., Naggert, J.K., North, M.A. & Nishina, P.M. A candidate gene for the mouse mutation tubby. Nature 380, 534–538 (1996).
Klebig, M.L., Wilkinson, J.E., Geisler, J.G. & Woychik, R.P. Ectopic expression of the agouti gene in transgenic mice causes obesity, features of type II diabetes and yellow fur. Proc. Natl Acad. Sci. USA 92, 4728–4732 (1995).
Montague, C.T. et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387, 903–908 (1997).
Clement, K. et al. Mutation in the human leptin receptor causes obesity and pituitary dysfunction. Nature 392, 398– 401 (1998).
Clement, K. et al. Indication for linkage of the human OB gene region with extreme obesity. Diabetes 45, 687– 690 (1996).
Reed, D.R. et al. Extreme obesity may be linked to markers flanking the human OB gene. Diabetes 45, 691– 694 (1996).
Norman, R.A., Bogardus, C. & Ravussin, E. Linkage between obesity and a marker near the tumour necrosis factor-* locus in Pima Indians. J. Clin. Invest. 96, 158–162 (1995).
Considine, R.V. et al. Evidence against either a premature stop codon or the absence of obese gene mRNA in human obesity. J. Clin. Invest. 95, 2986–2988 (1995).
Francke, S. et al. Genetic studies of the leptin receptor gene in morbidly obese French Caucasian families. Hum. Genet. 100, 491–496 (1997).
Norman, R.A. et al. Absence of linkage of obesity and energy metabolism to markers flanking homologues of rodent obesity genes in Pima Indians. Diabetes 45, 1229–1232 (1996).
Chagnon, Y.C., Perusse, L. & Bouchard, C. The human obesity gene map: the 1997 update. Obes. Res. 6, 76–92 (1998).
Lander, E. & Kuglyak, L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nature Genet. 11, 241–247 (1995).
Meunier, F., Philippi, A., Martinez, M. & Demenais, F. Affected sib-pair tests for linkage: Type 1 errors with dependent sib-pairs. Genet. Epidemiol. 14, 1107– 1111 (1997).
Tiret, L. et al. Segregation analysis of height-adjusted weight with generation- and age-dependent effects: the Nancy Family Study. Genet. Epidemiol. 9, 389–403 (1992).
Considine, R.V. et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N. Eng. J. Med. 334, 292–295 (1996).
O'Connell, J.R. & Weeks, D.E. The VITESSE algorithm for rapid exact multilocus linkage analysis via genotype set-recording and fuzzy inheritance. Nature Genet. 11, 402–408 (1995).
Kruglyak, L. & Lander, E.S. Complete multipoint sib-pair analysis of qualitative and quantitative traits. Am. J. Hum. Genet. 57, 439–454 (1995).
Tran, L.D., Elston, R.C., Keats, B.J.B. & Wilson, A.F. Sib-pair linkage program (SIBPAL). in S.A.G.E. Statistical Analysis for Genetic Epidemiology, Release 2.2 (Louisiana State University, New Orleans, 1994).
Haseman, J.K. & Elston, R.C. The investigation of linkage between a quantitative trait and a marker locus. Behav. Genet. 2, 3–19 (1972).
We thank the patients for their participation to this study. We also thank the Assistance Publique/Hôpitaux de Paris (AP/HP) and the Programme Hôspitalier de Recherche Clinique (PHRC) for their support. We are grateful for the constructive discussions and help with the statistical analyses by M. Lathrop and M. Farrall. J.H. and E.V. were supported through European grant program BIOMED2 BMH4-CT950662.
About this article
A Systematically Assembled Signature of Genes to be Deep-Sequenced for Their Associations with the Blood Pressure Response to Exercise
Obesity Reviews (2019)
The Journal of Physiology (2019)
Physiological Reviews (2018)
The Na+/Cl−-Coupled, Broad-Specific, Amino Acid Transporter SLC6A14 (ATB0,+): Emerging Roles in Multiple Diseases and Therapeutic Potential for Treatment and Diagnosis
The AAPS Journal (2018)