title: Evidence for the role of EPHX2 gene variants in anorexia nervosa.
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.
authors.affiliation: 1] The Scripps Translational Science Institute, La Jolla, CA, USA [2] Scripps Health, La Jolla, CA, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Scott-Van Zeeland
authors.affiliation: 1] The Scripps Translational Science Institute, La Jolla, CA, USA [2] Scripps Health, La Jolla, CA, USA.
authors.forename: C S
authors.initials: CS
authors.lastname: Bloss
authors.affiliation: 1] Scripps Health, La Jolla, CA, USA [2] Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Tewhey
authors.affiliation: 1] The Scripps Translational Science Institute, La Jolla, CA, USA [2] Scripps Health, La Jolla, CA, USA.
authors.forename: V
authors.initials: V
authors.lastname: Bansal
authors.affiliation: 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.
authors.forename: A
authors.initials: A
authors.lastname: Torkamani
authors.affiliation: 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.
authors.forename: O
authors.initials: O
authors.lastname: Libiger
authors.affiliation: Department of Pediatrics, The University of California, San Diego, La Jolla, CA, USA.
authors.forename: V
authors.initials: V
authors.lastname: Duvvuri
authors.affiliation: 1] The Scripps Translational Science Institute, La Jolla, CA, USA [2] Scripps Health, La Jolla, CA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Wineinger
authors.affiliation: The Scripps Translational Science Institute, La Jolla, CA, USA.
authors.forename: L
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authors.lastname: Galvez
authors.affiliation: 1] The Scripps Translational Science Institute, La Jolla, CA, USA [2] Scripps Health, La Jolla, CA, USA.
authors.forename: B F
authors.initials: BF
authors.lastname: Darst
authors.affiliation: Department of Pediatrics, The University of California, San Diego, La Jolla, CA, USA.
authors.forename: E N
authors.initials: EN
authors.lastname: Smith
authors.affiliation: 1] The Scripps Translational Science Institute, La Jolla, CA, USA [2] Scripps Health, La Jolla, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Carson
authors.affiliation: 1] The Scripps Translational Science Institute, La Jolla, CA, USA [2] Scripps Health, La Jolla, CA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Pham
authors.affiliation: 1] The Scripps Translational Science Institute, La Jolla, CA, USA [2] Scripps Health, La Jolla, CA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Phillips
authors.affiliation: 1] The Scripps Translational Science Institute, La Jolla, CA, USA [2] Scripps Health, La Jolla, CA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Villarasa
authors.affiliation: 1] The Scripps Translational Science Institute, La Jolla, CA, USA [2] Scripps Health, La Jolla, CA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Tisch
authors.affiliation: 1] The Scripps Translational Science Institute, La Jolla, CA, USA [2] Scripps Health, La Jolla, CA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: S
authors.initials: S
authors.lastname: Levy
authors.affiliation: 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.
authors.forename: S
authors.initials: S
authors.lastname: Murray
authors.affiliation: Department of Epidemiology, Tulane University, New Orleans, LA, USA.
authors.forename: W
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Epidemiology, Tulane University, New Orleans, LA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Srinivasan
authors.affiliation: Department of Epidemiology, Tulane University, New Orleans, LA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Berenson
authors.affiliation: Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: H
authors.initials: H
authors.lastname: Brandt
authors.affiliation: Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: S
authors.initials: S
authors.lastname: Crawford
authors.affiliation: Department of Psychiatry, University of Minnesota, Minneapolis, MN, USA.
authors.forename: S
authors.initials: S
authors.lastname: Crow
authors.affiliation: Roseneck Hospital for Behavioral Medicine, Prien, Germany.
authors.forename: M M
authors.initials: MM
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authors.affiliation: Eating Disorder Research Program Weill Cornell Medical College, White Plains, NY, USA.
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authors.affiliation: Eating Recovery Center, Denver, CO, USA.
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authors.lastname: Johnson
authors.affiliation: 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.
authors.forename: A S
authors.initials: AS
authors.lastname: Kaplan
authors.affiliation: Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: M
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authors.affiliation: 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.
authors.forename: J E
authors.initials: JE
authors.lastname: Mitchell
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Strober
authors.affiliation: Department of Psychiatry, Neurobiology, Pharmacology, and Biotechnology, University of Pisa, Pisa, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Rotondo
authors.affiliation: Department of Academic Psychiatry, Bermondsey Wing Guys Hospital, University of London, London, UK.
authors.forename: J
authors.initials: J
authors.lastname: Treasure
authors.affiliation: 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.
authors.forename: D B
authors.initials: DB
authors.lastname: Woodside
authors.affiliation: 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.
authors.forename: C M
authors.initials: CM
authors.lastname: Bulik
authors.affiliation: Department of Psychology, Florida State University, Tallahassee, FL, USA.
authors.forename: P
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authors.lastname: Keel
authors.affiliation: Department of Psychology, Michigan State University, East Lansing, MI, USA.
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authors.initials: KL
authors.lastname: Klump
authors.affiliation: Clinical Psychology Program, American School of Professional Psychology at Argosy University, Washington, DC, USA.
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authors.initials: L
authors.lastname: Lilenfeld
authors.affiliation: Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Plotnicov
authors.affiliation: 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.
authors.forename: E J
authors.initials: EJ
authors.lastname: Topol
authors.affiliation: Department of Pediatrics, The University of California, San Diego, La Jolla, CA, USA.
authors.forename: P B
authors.initials: PB
authors.lastname: Shih
authors.affiliation: Laboratory of Neuroenergetics and Cellular Dynamics, The University of Lausanne, Lausanne, Switzerland.
authors.forename: P
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authors.lastname: Magistretti
authors.affiliation: Center for Health Sciences, SRI International, Menlo Park, CA, USA.
authors.forename: A W
authors.initials: AW
authors.lastname: Bergen
authors.affiliation: Department of Psychiatry, The University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: W
authors.initials: W
authors.lastname: Berrettini
authors.affiliation: Department of Pediatrics, The University of California, San Diego, La Jolla, CA, USA.
authors.forename: W
authors.initials: W
authors.lastname: Kaye
authors.affiliation: 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.
authors.forename: N J
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mesh_terms: D000328:Adult; D000856:Anorexia Nervosa / Q000235:genetics* / Q000378:metabolism; D015992:Body Mass Index; D016022:Case-Control Studies; D002784:Cholesterol / Q000378:metabolism; D015331:Cohort Studies; D004851:Epoxide Hydrolases / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011594:Psychometrics; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: D002784:Cholesterol; D004851:Epoxide Hydrolases; C506428:EPHX2 protein, human