American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 124B:68–72 (2004) Combined Family Trio and Case-Control Analysis of the COMT Val158Met Polymorphism in European Patients With Anorexia Nervosa M. Gabrovsek, 1,3 * M. Brecelj-Anderluh, 2 L. Bellodi, 6 E. Cellini, 7 D. Di Bella, 6 X. Estivill, 5 F. Fernandez-Aranda, 5 B. Freeman, 3 F. Geller, 8 M. Gratacos, 5 R. Haigh, 3 J. Hebebrand, 8 A. Hinney, 8 J. Holliday, 3 X. Hu, 3 A. Karwautz, 4 B. Nacmias, 7 M. Ribases, 5 H. Remschmidt, 8 R. Komel, 1 S. Sorbi, 7 M. Tomori, 2 J. Treasure, 3 G. Wagner, 4 J. Zhao, 3 and D.A. Collier 3 1 Medical Centre for Molecular Biology, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia 2 Psychiatric Clinic Ljubljana, Ljubljana, Slovenia 3 Eating Disorders Unit, Section of Genetics and Social, Genetic and Developmental Psychiatry Research Centre, Institute of Psychiatry, De Crespigny Park, Denmark Hill, London, United Kingdom 4 University Clinic of Neuropsychiatry of Childhood and Adolescence, Vienna, Austria 5 Department of Psychiatry, Hospital Principes D’Espana, Barcelona, Spain 6 Fondazione Centro del Monte Tabor Dept Psychiatry IV-DSNP, Milan, Italy 7 University of Florence, Department of Neurology and Psychiatric Services, Florence, Italy 8 Clinical Research Group, Department of Child and Adolescent Psychiatry, Philipps-University of Marburg, Marburg, Germany The high activity Val158 (H) allele of the dopamine-metabolizing enzyme catechol-O- methyltransferase (COMT) was associated with anorexia nervosa (AN) in a recent family trio-based study of patients from Israel. In an attempt to replicate this finding, we performed a combined family trio and case-control study in an European popula- tion from seven centers in six different countries (Austria, Germany, Great Britain, Italy [Milan], Italy [Florence], Slovenia, and Spain), together contributing a total of 372 family trios, 684 controls and 266 cases. TDT analyses of high (H) and low (L) alleles in family trios showed that H allele and L allele were each transmitted 101 times (x 2 ¼ 0, ns). Allele-wise case-control analysis using sepa- rate samples simply combined from the centers was also not significant, with the frequencies of the H allele 50% in cases and same in controls. Stratified analysis of data from all centers gave an odds ratio of 0.98 (Cornfield 95% confidence limits 0.78–1.24). Analysis by genotype was likewise not signi- ficant (overall x 2 ¼ 0.42). Because we were not able to support the primary hypothesis that Val158Met is a risk factor for AN, we did not perform secondary analysis of minimum body mass index (mBMI), age at onset or illness subtype (restricting or binge purging anorexia). Overall we found no support for the hypothesis that the Val158 allele of COMT gene is associated with AN in our combined European sample. ß 2003 Wiley-Liss, Inc. KEY WORDS: eating disorders; anorexia nervosa; catechol-O-methyl- transferase (COMT); candi- date genes; dopamine INTRODUCTION Anorexia nervosa (AN) is a complex psychiatric disorder with both genetic and environmental causes [Bulik et al., 2000; Devlin et al., 2002]. It is characterized by failure to maintain body weight at a minimally normal level, intense fear of weight gain, disturbance in the way body shape or weight is experienced, and amenorrhea in postmenarcheal females [Gelder et al., EC Framework V ‘Factors in Healthy Eating’ consortium coordinated by Janet Treasure and David Collier. Grant sponsor: EC Framework V; Grant number: QLK1-1999- 916; Grant sponsor: PPP Healthcare Trust; Grant number: 1206/ 87; Grant sponsor: Slovenian Ministry of Education, Science and Sports; Grant sponsor: Fondo de Investigacio ´n Sanitario; Grant number: FIS 01/1558. *Correspondence to: M. Gabrovsek, Medical Centre for Molec- ular Biology, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia. E-mail: mgabrovsek@mf.uni-lj.si Received 16 September 2002; Accepted 29 April 2003 DOI 10.1002/ajmg.b.20085 ß 2003 Wiley-Liss, Inc.