American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 147B:1547–1553 (2008) Attention Deficit Hyperactivity Disorder in Obese Melanocortin-4-Receptor (MC4R) Deficient Subjects: A Newly Described Expression of MC4R Deficiency Anat Agranat-Meged, 1 * Yoad Ghanadri, 1 Iris Eisenberg, 2 Ziva Ben Neriah, 3 Eva Kieselstein-Gross, 4 and Stella Mitrani-Rosenbaum 2 1 Department of Child and Adolescent Psychiatry, Hadassah Hebrew University Medical Center, Jerusalem, Israel 2 Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Medical Center, Jerusalem, Israel 3 Department of Human Genetics, Hadassah Hebrew University Medical Center, Jerusalem, Israel 4 Department of Pediatrics, Hadassah Hebrew University Medical Center, Jerusalem, Israel Attention deficit hyperactivity disorder (ADHD) is a heterogeneous highly heritable disorder which has recently been described to be com- orbid in obese subjects. This study investigated phenotype/genotype associations in a consangui- neous family with genetic obesity due to the melanocortin-4-receptor (MC4R) (C271R) muta- tion. MC4R deficiency disrupts hunger/ satiety regulation resulting in abnormal eating behaviors. To date, the behavioral/psychiatric characteristics of MC4R deficiency have not been described except for a possible association with Binge Eating Disorder. Twenty-nine subjects of a family known to carry the MC4R (C271R) mutation, were genotyped for the mutation and underwent extensive evaluations in search for physical/psychiatric phenotype characteris- tics. Subjects originated from proband nuclear families with morbid obese children (BMI percentile > 97%). All probands were homozygous for the MC4R (C271R) mutation. ADHD preva- lence was higher than expected only in the groups carrying the homozygous or heterozygous muta- tion (P ¼ 0.00057, 0.0028, respectively). An obvious difference was observed between the homozygous group and the rest of the family in terms of obesity: homozygous subjects had childhood morbid obesity whereas heterozygous subjects included lean, normal weight and later onset obese sub- jects. A significant difference was found in ADHD prevalence between the homozygous MC4R (C271R) group (80%) and the rest of the family (22%) (P ¼ 0.033) and a significant trend was found between ADHD prevalence and the number of MC4R (C271R) alleles (P ¼ 0.0267). We conclude that in our sample, the MC4R (C271R) mutation causing obesity, is in association with ADHD. Identifying specific subgroups in which the comorbidity of obesity and ADHD occur may contribute to the understanding of the underlying molecular mechanisms. ß 2008 Wiley-Liss, Inc. KEY WORDS: attention deficit hyperactivity disorder; genetics behavioral; obesity; melanocortin-4-receptor Please cite this article as follows: Agranat Meged A, Ghanadri Y, Eisenberg I, Ben Neriah Z, Kieselstein- Gross E, Mitrani-Rosenbaum S. 2008. Attention Deficit Hyperactivity Disorder in Obese Melanocortin-4- Receptor (MC4R) Deficient Subjects: A Newly Described Expression of MC4R Deficiency. Am J Med Genet Part B 147B:1547 – 1553. INTRODUCTION Attention deficit hyperactivity disorder (ADHD) is a preva- lent disorder with an estimated heritability rate of 76% [Biederman and Faraone, 2005]. Recently, a possible associa- tion between obesity and comorbid ADHD has been described both in adults and in children [Alfas, 2002; Agranat-Meged et al., 2005; Fleming et al., 2005; Lam and Yang, 2007]. In a few studies, the association of obesity and ADHD was found in a subset of obese individuals with Binge Eating Disorder (BED) [Cortese et al., 2007]. In all the above studies the sample consisted of subjects which were ascertained for obesity and then examined for ADHD. The association of obesity and ADHD was described also in studies in which subjects were ascertained for ADHD and then examined for their weight. In these studies, ADHD diagnosis was found to be in association with overweight and obesity [Holtkamp et al., 2004; Hubel et al., 2006]. Suggestions have been made for the underlying mechanisms responsible for the association between obesity and ADHD. For example a possible association with the dopamine D4 receptor gene [Levitan et al., 2004]. However, this study referred only to Seasonal Affective Disorder patients. ADHD and obesity are both highly heterogeneous disorders. In search for the molecular mechanisms of the association of ADHD and obesity it is important to identify the specific subgroups in which the association occurs. The prevalence of obesity is rising around the world and has become an epidemic [WHO Press, 2000]. Environmental factors contribute to this epidemic with a lifestyle encouraging increased caloric intake and reduced physical activity [Farooqi and O’Rahilly, 2006]. However, there is accumulating evidence that body weight is highly heritable with a heritable compo- nent as high as 40 – 70% [Farooqi and O’Rahilly, 2006]. Research on the genetics of obesity revealed that eating behaviors play a central role in the development of obesity and that these behaviors are genetically determined. Thus, the *Correspondence to: Anat Agranat-Meged, 36 Metudela St., Jerusalem 92306, Israel. E-mail: anatagranat@013.net Received 14 April 2008; Accepted 8 July 2008 DOI 10.1002/ajmg.b.30842 Published online 5 September 2008 in Wiley InterScience (www.interscience.wiley.com) ß 2008 Wiley-Liss, Inc.