doi: 10.1111/j.1469-1809.2005.00228.x Obesity is Associated with Genetic Variants That Alter Dopamine Availability A. C. Need 1 , K. R. Ahmadi 1 , T. D. Spector 2 and D. B. Goldstein 1,* 1 Department of Biology, University College London, The Darwin Building, Gower Street, London WC1E 6BT 2 Twin Research & Genetic Epidemiology Unit, St Thomas’ Hospital, London SE1 Summary Human and animal studies have implicated dopamine in appetite regulation, and family studies have shown that BMI has a strong genetic component. Dopamine availability is controlled largely by three enzymes: COMT, MAOA and MAOB, and by the dopamine transporter SLC6A3, and each gene has a well-characterized functional variant. Here we look at these four functional polymorphisms together, to investigate how heritable variation in dopamine levels influences the risk of obesity in a cohort of 1150, including 240 defined as obese (BMI ≥ 30). The COMT and SLC6A3 polymorphisms showed no association with either weight, BMI or obesity risk. We found, however, that both MAOA and MAOB show an excess of the low-activity genotypes in obese individuals (MAOA: χ 2 = 15.45, p = 0.004; MAOB: χ 2 = 8.05, p = 0.018). Additionally, the MAOA genotype was significantly associated with both weight (p = 0.0005) and BMI (p = 0.001). When considered together, the ‘at risk genotype’ - low activity genotypes at both the MAOA and MAOB loci - shows a relative risk for obesity of 5.01. These results have not been replicated and, given the experience of complex trait genetics, warrant caution in interpretation. In implicating both the MAOA and MOAB variants, however, this study provides the first indication that dopamine availability (as opposed to other effects of MAOA) is involved in human obesity. It is therefore a priority to assess the associations in replication datasets. Introduction Obesity, generally defined as a body mass index (BMI) of 30 or above, is one of the biggest health problems in our society today. It is now clearly established that obesity is an important risk factor for a range of com- mon diseases including coronary heart disease, type 2 diabetes, osteoarthritis, and some forms of cancer (Kopelman, 2000; Manson et al. 1990). Although the current epidemic of obesity is clearly driven by lifestyle factors, such as a high fat diet and lack of exercise, fam- ily and twin studies have shown that BMI has a strong ∗ Corresponding author: David B. Goldstein, Center for Popu- lation Genomics and Pharmacogenetics, Duke Institute for Genome Sciences and Policy, Duke University, 4006 GSRB II, 103 Research Drive, DUMC Box 3471, Durham, NC 27710. Tel: 1 919 684 0896; Fax: 1 919 668 6787. E-mail: d.goldstein@duke.edu genetic component (Maes et al. 1997; Schousboe et al. 2003; Stunkard et al. 1990). There is evidence in both animal and human stud- ies that dopamine (DA) plays a role in obesity through regulation of appetite. Dopamine-deficient tyrosine ki- nase knockout mice are aphagic, and do not survive unless DA synthesis is restored to the dorsal striatum (Szczypka et al. 1999a,b, 2001; Zhou & Palmiter, 1995). Microdialysis experiments have shown that DA release in the hypothalamus regulates food intake, with the lateral hypothalamic area (LHA) and the ventrome- dial nucleus (VMN) working in concert to control meal size and frequency (Meguid et al. 2000). Ad- ditionally, DA is thought to reflect the reward prop- erties of food through the mesolimbic dopaminergic system (Martel & Fantino, 1996a,b). Obese Zucker rats consume larger meals, and release more DA in the LHA whilst eating than lean rats (Yang & Meguid, 1995). C  2005 The Authors Annals of Human Genetics (2006) 70,293–303 293 Journal compilation C  2005 University College London