Evidence for the role of EPHX2 gene variants in anorexia nervosa
Date Published: 9/13
Abstract:Anorexia nervosa (AN) and related eating disorders are complex, multifactorial neuropsychiatric conditions with likely rare and common genetic and environmental determinants. To identify genetic variants associated with AN, we pursued a series of sequencing and genotyping studies focusing on the coding regions and upstream sequence of 152 candidate genes in a total of 1205 AN cases and 1948 controls. We identified individual variant associations in the Estrogen Receptor- (ESR2) gene, as well as a set of rare and common variants in the Epoxide Hydrolase 2 (EPHX2) gene, in an initial sequencing study of 261 early-onset severe AN cases and 73 controls (P¼0.0004). The association of EPHX2 variants was further delineated in: (1) a pooling-based replication study involving an additional 500 AN patients and 500 controls (replication set P¼0.00000016); (2) single-locus studies in a cohort of 386 previously genotyped broadly defined AN cases and 295 female population controls from the Bogalusa Heart Study (BHS) and a cohort of 58 individuals with self-reported eating disturbances and 851 controls (combined smallest single locus Po0.01). As EPHX2 is known to influence cholesterol metabolism, and AN is often associated with elevated cholesterol levels, we also investigated the association of EPHX2 variants and longitudinal body mass index (BMI) and cholesterol in BHS female and male subjects (N¼229) and found evidence for a modifying effect of a subset of variants on the relationship between cholesterol and BMI (Po0.01). These findings suggest a novel association of gene variants within EPHX2 to susceptibility to AN and provide a foundation for future study of this important yet poorly understood condition.
AA Scott-Van Zeeland1,2, CS Bloss1,2, R Tewhey2,3, V Bansal1,2, A Torkamani1,2,3, O Libiger1,3, V Duvvuri4, N Wineinger1,2, L Galvez1, BF Darst1,2, EN Smith4, A Carson1,2, P Pham1,2, T Phillips1,2, N Villarasa1,2, R Tisch1,2, G Zhang1,2, S Levy1,2,3, S Murray1,2,3, W Chen5, S Srinivasan5, G Berenson5, H Brandt6, S Crawford6, S Crow7, MM Fichter8, KA Halmi9, C Johnson10, AS Kaplan11,12,13, M La Via14, JE Mitchell15,16, M Strober17, A Rotondo18, J Treasure19, DB Woodside12,13,20, CM Bulik14,21, P Keel20, KL Klump22, L Lilenfeld23, K Plotnicov24, EJ Topol1,2,3, PB Shih4, P Magistretti25, AW Bergen26, W Berrettini27, W Kaye4 and NJ Schork1,2,3
1The Scripps Translational Science Institute, La Jolla, CA, USA; 2Scripps Health, La Jolla, CA, USA; 3Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA; 4Department of Pediatrics, The University of California, San Diego, La Jolla, CA, USA; 5Department of Epidemiology, Tulane University, New Orleans, LA, USA; 6Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA; 7Department of Psychiatry, University of Minnesota, Minneapolis, MN, USA; 8Roseneck Hospital for Behavioral Medicine, Prien, Germany; 9Eating Disorder Research Program Weill Cornell Medical College, White Plains, NY, USA; 10Eating Recovery Center, Denver, CO, USA; 11Center for Addiction and Mental Health, Toronto, ON, Canada; 12Department of Psychiatry, Toronto General Hospital, University Health Network, Toronto, ON, Canada; 13Department of Psychiatry, University of Toronto, Toronto, ON, Canada; 14Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 15Neuropsychiatric Research Institute, Fargo, ND, USA; 16Department of Clinical Neuroscience, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA; 17Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA; 18Department of Psychiatry, Neurobiology, Pharmacology, and Biotechnology, University of Pisa, Pisa, Italy; 19Department of Academic Psychiatry, Bermondsey Wing Guys Hospital, University of London, London, UK; 20Department of Psychology, Florida State University, Tallahassee, FL, USA; 21Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 22Department of Psychology, Michigan State University, East Lansing, MI, USA; 23Clinical Psychology Program, American School of Professional Psychology at Argosy University, Washington, DC, USA; 24Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA; 25Laboratory of Neuroenergetics and Cellular Dynamics, The University of Lausanne, Lausanne, Switzerland; 26Center for Health Sciences, SRI International, Menlo Park, CA, USA and 27Department of Psychiatry, The University of Pennsylvania, Philadelphia, PA, USA. Correspondence: Dr NJ Schork, Department of Molecular and Experimental Medicine, The Scripps Research Institute, 3344 N Torrey Pines Court, Room 306, La Jolla, CA 92037, USA.