Evidence for the role of EPHX2 gene variants in anorexia nervosa

A. A. Scott-Van Zeeland, C. S. Bloss, R. Tewhey, V. Bansal, A. Torkamani, O. Libiger, V. Duvvuri, N. Wineinger, L. Galvez, B. F. Darst, E. N. Smith, A. Carson, P. Pham, T. Phillips, N. Villarasa, R. Tisch, G. Zhang, S. Levy, S. Murray, W. Chen & 27 others S. Srinivasan, G. Berenson, H. Brandt, S. Crawford, S. Crow, M. M. Fichter, K. A. Halmi, C. Johnson, A. S. Kaplan, M. La Via, J. E. Mitchell, M. Strober, A. Rotondo, J. Treasure, D. B. Woodside, C. M. Bulik, P. Keel, K. L. Klump, L. Lilenfeld, K. Plotnicov, E. J. Topol, P. B. Shih, P. Magistretti, A. W. Bergen, W. Berrettini, W. Kaye, N. J. Schork

Research output: Contribution to journalArticle

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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.

LanguageEnglish (US)
Pages724-732
Number of pages9
JournalMolecular Psychiatry
Volume19
Issue number6
DOIs
StatePublished - Jan 1 2014

Fingerprint

Anorexia Nervosa
Genes
Cholesterol
Body Mass Index
Epoxide Hydrolases
Population Control
Hypercholesterolemia
Estrogen Receptors
Cohort Studies
Eating

Keywords

  • anorexia nervosa
  • EPHX2
  • genomics
  • hyperlipidemia
  • pooling
  • sequencing

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Scott-Van Zeeland, A. A., Bloss, C. S., Tewhey, R., Bansal, V., Torkamani, A., Libiger, O., ... Schork, N. J. (2014). Evidence for the role of EPHX2 gene variants in anorexia nervosa. Molecular Psychiatry, 19(6), 724-732. DOI: 10.1038/mp.2013.91

Evidence for the role of EPHX2 gene variants in anorexia nervosa. / Scott-Van Zeeland, A. A.; Bloss, C. S.; Tewhey, R.; Bansal, V.; Torkamani, A.; Libiger, O.; Duvvuri, V.; Wineinger, N.; Galvez, L.; Darst, B. F.; Smith, E. N.; Carson, A.; Pham, P.; Phillips, T.; Villarasa, N.; Tisch, R.; Zhang, G.; Levy, S.; Murray, S.; Chen, W.; Srinivasan, S.; Berenson, G.; Brandt, H.; Crawford, S.; Crow, S.; Fichter, M. M.; Halmi, K. A.; Johnson, C.; Kaplan, A. S.; La Via, M.; Mitchell, J. E.; Strober, M.; Rotondo, A.; Treasure, J.; Woodside, D. B.; Bulik, C. M.; Keel, P.; Klump, K. L.; Lilenfeld, L.; Plotnicov, K.; Topol, E. J.; Shih, P. B.; Magistretti, P.; Bergen, A. W.; Berrettini, W.; Kaye, W.; Schork, N. J.

In: Molecular Psychiatry, Vol. 19, No. 6, 01.01.2014, p. 724-732.

Research output: Contribution to journalArticle

Scott-Van Zeeland, AA, Bloss, CS, Tewhey, R, Bansal, V, Torkamani, A, Libiger, O, Duvvuri, V, Wineinger, N, Galvez, L, Darst, BF, Smith, EN, Carson, A, Pham, P, Phillips, T, Villarasa, N, Tisch, R, Zhang, G, Levy, S, Murray, S, Chen, W, Srinivasan, S, Berenson, G, Brandt, H, Crawford, S, Crow, S, Fichter, MM, Halmi, KA, Johnson, C, Kaplan, AS, La Via, M, Mitchell, JE, Strober, M, Rotondo, A, Treasure, J, Woodside, DB, Bulik, CM, Keel, P, Klump, KL, Lilenfeld, L, Plotnicov, K, Topol, EJ, Shih, PB, Magistretti, P, Bergen, AW, Berrettini, W, Kaye, W & Schork, NJ 2014, 'Evidence for the role of EPHX2 gene variants in anorexia nervosa' Molecular Psychiatry, vol. 19, no. 6, pp. 724-732. DOI: 10.1038/mp.2013.91
Scott-Van Zeeland AA, Bloss CS, Tewhey R, Bansal V, Torkamani A, Libiger O et al. Evidence for the role of EPHX2 gene variants in anorexia nervosa. Molecular Psychiatry. 2014 Jan 1;19(6):724-732. Available from, DOI: 10.1038/mp.2013.91
Scott-Van Zeeland, A. A. ; Bloss, C. S. ; Tewhey, R. ; Bansal, V. ; Torkamani, A. ; Libiger, O. ; Duvvuri, V. ; Wineinger, N. ; Galvez, L. ; Darst, B. F. ; Smith, E. N. ; Carson, A. ; Pham, P. ; Phillips, T. ; Villarasa, N. ; Tisch, R. ; Zhang, G. ; Levy, S. ; Murray, S. ; Chen, W. ; Srinivasan, S. ; Berenson, G. ; Brandt, H. ; Crawford, S. ; Crow, S. ; Fichter, M. M. ; Halmi, K. A. ; Johnson, C. ; Kaplan, A. S. ; La Via, M. ; Mitchell, J. E. ; Strober, M. ; Rotondo, A. ; Treasure, J. ; Woodside, D. B. ; Bulik, C. M. ; Keel, P. ; Klump, K. L. ; Lilenfeld, L. ; Plotnicov, K. ; Topol, E. J. ; Shih, P. B. ; Magistretti, P. ; Bergen, A. W. ; Berrettini, W. ; Kaye, W. ; Schork, N. J./ Evidence for the role of EPHX2 gene variants in anorexia nervosa. In: Molecular Psychiatry. 2014 ; Vol. 19, No. 6. pp. 724-732
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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.",
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