Original Article

Molecular Psychiatry (2014) 19, 724–732; doi:10.1038/mp.2013.91; published online 3 September 2013

Evidence for the role of EPHX2 gene variants in anorexia nervosa
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A A Scott-Van Zeeland1,2, C S Bloss1,2, R Tewhey2,3, V Bansal1,2, A Torkamani1,2,3, O Libiger1,3, V Duvvuri4, N Wineinger1,2, L Galvez1, B F Darst1,2, E N 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, M M Fichter8, K A Halmi9, C Johnson10, A S Kaplan11,12,13, M La Via14, J E Mitchell15,16, M Strober17, A Rotondo18, J Treasure19, D B Woodside12,13,20, C M Bulik14,21, P Keel20, K L Klump22, L Lilenfeld23, K Plotnicov24, E J Topol1,2,3, P B Shih4, P Magistretti25, A W Bergen26, W Berrettini27, W Kaye4 and N J Schork1,2,3

  1. 1The Scripps Translational Science Institute, La Jolla, CA, USA
  2. 2Scripps Health, La Jolla, CA, USA
  3. 3Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA
  4. 4Department of Pediatrics, The University of California, San Diego, La Jolla, CA, USA
  5. 5Department of Epidemiology, Tulane University, New Orleans, LA, USA
  6. 6Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA
  7. 7Department of Psychiatry, University of Minnesota, Minneapolis, MN, USA
  8. 8Roseneck Hospital for Behavioral Medicine, Prien, Germany
  9. 9Eating Disorder Research Program Weill Cornell Medical College, White Plains, NY, USA
  10. 10Eating Recovery Center, Denver, CO, USA
  11. 11Center for Addiction and Mental Health, Toronto, ON, Canada
  12. 12Department of Psychiatry, Toronto General Hospital, University Health Network, Toronto, ON, Canada
  13. 13Department of Psychiatry, University of Toronto, Toronto, ON, Canada
  14. 14Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
  15. 15Neuropsychiatric Research Institute, Fargo, ND, USA
  16. 16Department of Clinical Neuroscience, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA
  17. 17Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA
  18. 18Department of Psychiatry, Neurobiology, Pharmacology, and Biotechnology, University of Pisa, Pisa, Italy
  19. 19Department of Academic Psychiatry, Bermondsey Wing Guys Hospital, University of London, London, UK
  20. 20Department of Psychology, Florida State University, Tallahassee, FL, USA
  21. 21Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
  22. 22Department of Psychology, Michigan State University, East Lansing, MI, USA
  23. 23Clinical Psychology Program, American School of Professional Psychology at Argosy University, Washington, DC, USA
  24. 24Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA
  25. 25Laboratory of Neuroenergetics and Cellular Dynamics, The University of Lausanne, Lausanne, Switzerland
  26. 26Center for Health Sciences, SRI International, Menlo Park, CA, USA
  27. 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. E-mail: nschork@scripps.edu

Received 11 February 2013; Revised 19 June 2013; Accepted 24 June 2013
Advance online publication 3 September 2013

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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-ß (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 (P=0.0004). 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 P=0.00000016); (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 P<0.01). 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 (N=229) and found evidence for a modifying effect of a subset of variants on the relationship between cholesterol and BMI (P<0.01). 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.

Keywords:

anorexia nervosa; EPHX2; genomics; hyperlipidemia; pooling; sequencing