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; 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

doi:10.1038/mp.2013.91

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. ChenS. 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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

60 Scopus citations

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.

Original language	English (US)
Pages (from-to)	724-732
Number of pages	9
Journal	Molecular Psychiatry
Volume	19
Issue number	6
DOIs	https://doi.org/10.1038/mp.2013.91
State	Published - Jun 2014

Keywords

EPHX2
anorexia nervosa
genomics
hyperlipidemia
pooling
sequencing

ASJC Scopus subject areas

Molecular Biology
Cellular and Molecular Neuroscience
Psychiatry and Mental health

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/mp.2013.91

Cite this

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., ... Schork, N. J. (2014). Evidence for the role of EPHX2 gene variants in anorexia nervosa. Molecular Psychiatry, 19(6), 724-732. https://doi.org/10.1038/mp.2013.91

@article{2879b52dd4b44e75925a851c4bc51322,

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.",

keywords = "EPHX2, anorexia nervosa, genomics, hyperlipidemia, pooling, sequencing",

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

note = "Funding Information: This study was made possible by a generous gift from the Price Foundation. AVZ, CSB, RT, VB, AT, AC, PP, TP, NV, RT, GZ, SL, SM and NJS are all supported in part by NIH grant 5 UL1 RR025774 and Scripps Genomic Medicine. NJS and his laboratory are also supported in part by NIH grants; 5 U01 DA024417, 5 R01 HL089655, 5 R01 DA030976, 5 R01 AG035020, 1 R01 MH093500, 2 U19 AI063603, 2 U19 AG023122, 5 P01 AG027734 as well as the Stand Up To Cancer Foundation. M Strober receives support from the Resnick Chair in Eating Disorders. B Shih is in part supported by 5K01DK087813-02, and CSB is in part supported by NIH grant 1R21HG005747-01. The Price Foundation Collaborative Group has been responsible for the data collection, curation, management and oversight of the DNA samples used in this report. The members of this group have also provided feedback on this and other reports making use of the samples.",

year = "2014",

month = jun,

doi = "10.1038/mp.2013.91",

language = "English (US)",

volume = "19",

pages = "724--732",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Nature Publishing Group",

number = "6",

}

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. https://doi.org/10.1038/mp.2013.91

TY - JOUR

T1 - Evidence for the role of EPHX2 gene variants in anorexia nervosa

AU - Scott-Van Zeeland, A. A.

AU - Bloss, C. S.

AU - Tewhey, R.

AU - Bansal, V.

AU - Torkamani, A.

AU - Libiger, O.

AU - Duvvuri, V.

AU - Wineinger, N.

AU - Galvez, L.

AU - Darst, B. F.

AU - Smith, E. N.

AU - Carson, A.

AU - Pham, P.

AU - Phillips, T.

AU - Villarasa, N.

AU - Tisch, R.

AU - Zhang, G.

AU - Levy, S.

AU - Murray, S.

AU - Chen, W.

AU - Srinivasan, S.

AU - Berenson, G.

AU - Brandt, H.

AU - Crawford, S.

AU - Crow, S.

AU - Fichter, M. M.

AU - Halmi, K. A.

AU - Johnson, C.

AU - Kaplan, A. S.

AU - La Via, M.

AU - Mitchell, J. E.

AU - Strober, M.

AU - Rotondo, A.

AU - Treasure, J.

AU - Woodside, D. B.

AU - Bulik, C. M.

AU - Keel, P.

AU - Klump, K. L.

AU - Lilenfeld, L.

AU - Plotnicov, K.

AU - Topol, E. J.

AU - Shih, P. B.

AU - Magistretti, P.

AU - Bergen, A. W.

AU - Berrettini, W.

AU - Kaye, W.

AU - Schork, N. J.

N1 - Funding Information: This study was made possible by a generous gift from the Price Foundation. AVZ, CSB, RT, VB, AT, AC, PP, TP, NV, RT, GZ, SL, SM and NJS are all supported in part by NIH grant 5 UL1 RR025774 and Scripps Genomic Medicine. NJS and his laboratory are also supported in part by NIH grants; 5 U01 DA024417, 5 R01 HL089655, 5 R01 DA030976, 5 R01 AG035020, 1 R01 MH093500, 2 U19 AI063603, 2 U19 AG023122, 5 P01 AG027734 as well as the Stand Up To Cancer Foundation. M Strober receives support from the Resnick Chair in Eating Disorders. B Shih is in part supported by 5K01DK087813-02, and CSB is in part supported by NIH grant 1R21HG005747-01. The Price Foundation Collaborative Group has been responsible for the data collection, curation, management and oversight of the DNA samples used in this report. The members of this group have also provided feedback on this and other reports making use of the samples.

PY - 2014/6

Y1 - 2014/6

N2 - 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.

AB - 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.

KW - EPHX2

KW - anorexia nervosa

KW - genomics

KW - hyperlipidemia

KW - pooling

KW - sequencing

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U2 - 10.1038/mp.2013.91

DO - 10.1038/mp.2013.91

M3 - Article

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AN - SCOPUS:84901258591

SN - 1359-4184

VL - 19

SP - 724

EP - 732

JO - Molecular Psychiatry

JF - Molecular Psychiatry

IS - 6

ER -

Evidence for the role of EPHX2 gene variants in anorexia nervosa

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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