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Mol Psychiatry. 2014 Jun;19(6):724-32. doi: 10.1038/mp.2013.91. Epub 2013 Sep 3.

Evidence for the role of EPHX2 gene variants in anorexia nervosa.

Author information

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

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.

PMID:
23999524
PMCID:
PMC3852189
DOI:
10.1038/mp.2013.91
[Indexed for MEDLINE]
Free PMC Article

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