Evidence for three genetic loci involved in both anorexia nervosa risk and variation of body mass index

A. Hinney, M. Kesselmeier, S. Jall, A. L. Volckmar, M. Föcker, J. Antel, I. M. Heid, T. W. Winkler, S. F.A. Grant, Y. Guo, A. W. Bergen, W. Kaye, W. Berrettini, H. Hakonarson, B. Herpertz-Dahlmann, M. De Zwaan, W. Herzog, S. Ehrlich, S. Zipfel, K. M. Egberts & 36 others R. Adan, M. Brandys, A. Van Elburg, V. Boraska Perica, T. D. Müller, M. H. Tschöp, E. Zeggini, C. M. Bulik, D. Collier, A. Scherag, T. D. Müller, J. Hebebrand, Vesna Boraska Perica, Christopher S. Franklin, James A.B. Floyd, Laura M. Thornton, Laura M. Huckins, Lorraine Southam, N. William Rayner, Ioanna Tachmazidou, Kelly L. Klump, Janet Treasure, Cathryn M. Lewis, Ulrike Schmidt, Federica Tozzi, Kirsty Iezebrink, Johannes Hebebrand, Philip Gorwood, Roger A.H. Adan, M. J. Econs, GCAN, WTCCC3, GIANT, EGG, Price Foundation Collaborative Group, Children’s Hospital of Philadelphia/Price Foundation

    Research output: Contribution to journalArticle

    21 Citations (Scopus)

    Abstract

    The maintenance of normal body weight is disrupted in patients with anorexia nervosa (AN) for prolonged periods of time. Prior to the onset of AN, premorbid body mass index (BMI) spans the entire range from underweight to obese. After recovery, patients have reduced rates of overweight and obesity. As such, loci involved in body weight regulation may also be relevant for AN and vice versa. Our primary analysis comprised a cross-trait analysis of the 1000 single-nucleotide polymorphisms (SNPs) with the lowest P-values in a genome-wide association meta-analysis (GWAMA) of AN (GCAN) for evidence of association in the largest published GWAMA for BMI (GIANT). Subsequently we performed sex-stratified analyses for these 1000 SNPs. Functional ex vivo studies on four genes ensued. Lastly, a look-up of GWAMA-derived BMI-related loci was performed in the AN GWAMA. We detected significant associations (P-values <5 × 10-5, Bonferroni-corrected P<0.05) for nine SNP alleles at three independent loci. Interestingly, all AN susceptibility alleles were consistently associated with increased BMI. None of the genes (chr. 10: CTBP2, chr. 19: CCNE1, chr. 2: CARF and NBEAL1; the latter is a region with high linkage disequilibrium) nearest to these SNPs has previously been associated with AN or obesity. Sex-stratified analyses revealed that the strongest BMI signal originated predominantly from females (chr. 10 rs1561589; Poverall: 2.47 × 10-06/Pfemales: 3.45 × 10-07/Pmales: 0.043). Functional ex vivo studies in mice revealed reduced hypothalamic expression of Ctbp2 and Nbeal1 after fasting. Hypothalamic expression of Ctbp2 was increased in diet-induced obese (DIO) mice as compared with age-matched lean controls. We observed no evidence for associations for the look-up of BMI-related loci in the AN GWAMA. A cross-trait analysis of AN and BMI loci revealed variants at three chromosomal loci with potential joint impact. The chromosome 10 locus is particularly promising given that the association with obesity was primarily driven by females. In addition, the detected altered hypothalamic expression patterns of Ctbp2 and Nbeal1 as a result of fasting and DIO implicate these genes in weight regulation.

    Original languageEnglish (US)
    Pages (from-to)192-201
    Number of pages10
    JournalMolecular Psychiatry
    Volume22
    Issue number2
    DOIs
    StatePublished - Feb 1 2017

    Fingerprint

    Genetic Loci
    Anorexia Nervosa
    Body Mass Index
    Genome-Wide Association Study
    Meta-Analysis
    Single Nucleotide Polymorphism
    Obesity
    Fasting
    Alleles
    Genes
    Diet
    Ideal Body Weight
    Obese Mice
    Chromosomes, Human, Pair 10
    Thinness
    Linkage Disequilibrium
    Joints
    Body Weight
    Maintenance
    Weights and Measures

    All Science Journal Classification (ASJC) codes

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

    Cite this

    Hinney, A., Kesselmeier, M., Jall, S., Volckmar, A. L., Föcker, M., Antel, J., ... Children’s Hospital of Philadelphia/Price Foundation (2017). Evidence for three genetic loci involved in both anorexia nervosa risk and variation of body mass index. Molecular Psychiatry, 22(2), 192-201. https://doi.org/10.1038/mp.2016.71

    Evidence for three genetic loci involved in both anorexia nervosa risk and variation of body mass index. / Hinney, A.; Kesselmeier, M.; Jall, S.; Volckmar, A. L.; Föcker, M.; Antel, J.; Heid, I. M.; Winkler, T. W.; Grant, S. F.A.; Guo, Y.; Bergen, A. W.; Kaye, W.; Berrettini, W.; Hakonarson, H.; Herpertz-Dahlmann, B.; De Zwaan, M.; Herzog, W.; Ehrlich, S.; Zipfel, S.; Egberts, K. M.; Adan, R.; Brandys, M.; Van Elburg, A.; Boraska Perica, V.; Müller, T. D.; Tschöp, M. H.; Zeggini, E.; Bulik, C. M.; Collier, D.; Scherag, A.; Müller, T. D.; Hebebrand, J.; Perica, Vesna Boraska; Franklin, Christopher S.; Floyd, James A.B.; Thornton, Laura M.; Huckins, Laura M.; Southam, Lorraine; Rayner, N. William; Tachmazidou, Ioanna; Klump, Kelly L.; Treasure, Janet; Lewis, Cathryn M.; Schmidt, Ulrike; Tozzi, Federica; Iezebrink, Kirsty; Hebebrand, Johannes; Gorwood, Philip; Adan, Roger A.H.; Econs, M. J.; GCAN; WTCCC3; GIANT; EGG; Price Foundation Collaborative Group; Children’s Hospital of Philadelphia/Price Foundation.

    In: Molecular Psychiatry, Vol. 22, No. 2, 01.02.2017, p. 192-201.

    Research output: Contribution to journalArticle

    Hinney, A, Kesselmeier, M, Jall, S, Volckmar, AL, Föcker, M, Antel, J, Heid, IM, Winkler, TW, Grant, SFA, Guo, Y, Bergen, AW, Kaye, W, Berrettini, W, Hakonarson, H, Herpertz-Dahlmann, B, De Zwaan, M, Herzog, W, Ehrlich, S, Zipfel, S, Egberts, KM, Adan, R, Brandys, M, Van Elburg, A, Boraska Perica, V, Müller, TD, Tschöp, MH, Zeggini, E, Bulik, CM, Collier, D, Scherag, A, Müller, TD, Hebebrand, J, Perica, VB, Franklin, CS, Floyd, JAB, Thornton, LM, Huckins, LM, Southam, L, Rayner, NW, Tachmazidou, I, Klump, KL, Treasure, J, Lewis, CM, Schmidt, U, Tozzi, F, Iezebrink, K, Hebebrand, J, Gorwood, P, Adan, RAH, Econs, MJ, GCAN, WTCCC3, GIANT, EGG, Price Foundation Collaborative Group & Children’s Hospital of Philadelphia/Price Foundation 2017, 'Evidence for three genetic loci involved in both anorexia nervosa risk and variation of body mass index', Molecular Psychiatry, vol. 22, no. 2, pp. 192-201. https://doi.org/10.1038/mp.2016.71
    Hinney, A. ; Kesselmeier, M. ; Jall, S. ; Volckmar, A. L. ; Föcker, M. ; Antel, J. ; Heid, I. M. ; Winkler, T. W. ; Grant, S. F.A. ; Guo, Y. ; Bergen, A. W. ; Kaye, W. ; Berrettini, W. ; Hakonarson, H. ; Herpertz-Dahlmann, B. ; De Zwaan, M. ; Herzog, W. ; Ehrlich, S. ; Zipfel, S. ; Egberts, K. M. ; Adan, R. ; Brandys, M. ; Van Elburg, A. ; Boraska Perica, V. ; Müller, T. D. ; Tschöp, M. H. ; Zeggini, E. ; Bulik, C. M. ; Collier, D. ; Scherag, A. ; Müller, T. D. ; Hebebrand, J. ; Perica, Vesna Boraska ; Franklin, Christopher S. ; Floyd, James A.B. ; Thornton, Laura M. ; Huckins, Laura M. ; Southam, Lorraine ; Rayner, N. William ; Tachmazidou, Ioanna ; Klump, Kelly L. ; Treasure, Janet ; Lewis, Cathryn M. ; Schmidt, Ulrike ; Tozzi, Federica ; Iezebrink, Kirsty ; Hebebrand, Johannes ; Gorwood, Philip ; Adan, Roger A.H. ; Econs, M. J. ; GCAN ; WTCCC3 ; GIANT ; EGG ; Price Foundation Collaborative Group ; Children’s Hospital of Philadelphia/Price Foundation. / Evidence for three genetic loci involved in both anorexia nervosa risk and variation of body mass index. In: Molecular Psychiatry. 2017 ; Vol. 22, No. 2. pp. 192-201.
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    title = "Evidence for three genetic loci involved in both anorexia nervosa risk and variation of body mass index",
    abstract = "The maintenance of normal body weight is disrupted in patients with anorexia nervosa (AN) for prolonged periods of time. Prior to the onset of AN, premorbid body mass index (BMI) spans the entire range from underweight to obese. After recovery, patients have reduced rates of overweight and obesity. As such, loci involved in body weight regulation may also be relevant for AN and vice versa. Our primary analysis comprised a cross-trait analysis of the 1000 single-nucleotide polymorphisms (SNPs) with the lowest P-values in a genome-wide association meta-analysis (GWAMA) of AN (GCAN) for evidence of association in the largest published GWAMA for BMI (GIANT). Subsequently we performed sex-stratified analyses for these 1000 SNPs. Functional ex vivo studies on four genes ensued. Lastly, a look-up of GWAMA-derived BMI-related loci was performed in the AN GWAMA. We detected significant associations (P-values <5 × 10-5, Bonferroni-corrected P<0.05) for nine SNP alleles at three independent loci. Interestingly, all AN susceptibility alleles were consistently associated with increased BMI. None of the genes (chr. 10: CTBP2, chr. 19: CCNE1, chr. 2: CARF and NBEAL1; the latter is a region with high linkage disequilibrium) nearest to these SNPs has previously been associated with AN or obesity. Sex-stratified analyses revealed that the strongest BMI signal originated predominantly from females (chr. 10 rs1561589; Poverall: 2.47 × 10-06/Pfemales: 3.45 × 10-07/Pmales: 0.043). Functional ex vivo studies in mice revealed reduced hypothalamic expression of Ctbp2 and Nbeal1 after fasting. Hypothalamic expression of Ctbp2 was increased in diet-induced obese (DIO) mice as compared with age-matched lean controls. We observed no evidence for associations for the look-up of BMI-related loci in the AN GWAMA. A cross-trait analysis of AN and BMI loci revealed variants at three chromosomal loci with potential joint impact. The chromosome 10 locus is particularly promising given that the association with obesity was primarily driven by females. In addition, the detected altered hypothalamic expression patterns of Ctbp2 and Nbeal1 as a result of fasting and DIO implicate these genes in weight regulation.",
    author = "A. Hinney and M. Kesselmeier and S. Jall and Volckmar, {A. L.} and M. F{\"o}cker and J. Antel and Heid, {I. M.} and Winkler, {T. W.} and Grant, {S. F.A.} and Y. Guo and Bergen, {A. W.} and W. Kaye and W. Berrettini and H. Hakonarson and B. Herpertz-Dahlmann and {De Zwaan}, M. and W. Herzog and S. Ehrlich and S. Zipfel and Egberts, {K. M.} and R. Adan and M. Brandys and {Van Elburg}, A. and {Boraska Perica}, V. and M{\"u}ller, {T. D.} and Tsch{\"o}p, {M. H.} and E. Zeggini and Bulik, {C. M.} and D. Collier and A. Scherag and M{\"u}ller, {T. D.} and J. Hebebrand and Perica, {Vesna Boraska} and Franklin, {Christopher S.} and Floyd, {James A.B.} and Thornton, {Laura M.} and Huckins, {Laura M.} and Lorraine Southam and Rayner, {N. William} and Ioanna Tachmazidou and Klump, {Kelly L.} and Janet Treasure and Lewis, {Cathryn M.} and Ulrike Schmidt and Federica Tozzi and Kirsty Iezebrink and Johannes Hebebrand and Philip Gorwood and Adan, {Roger A.H.} and Econs, {M. J.} and GCAN and WTCCC3 and GIANT and EGG and {Price Foundation Collaborative Group} and {Children’s Hospital of Philadelphia/Price Foundation}",
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    T1 - Evidence for three genetic loci involved in both anorexia nervosa risk and variation of body mass index

    AU - Hinney, A.

    AU - Kesselmeier, M.

    AU - Jall, S.

    AU - Volckmar, A. L.

    AU - Föcker, M.

    AU - Antel, J.

    AU - Heid, I. M.

    AU - Winkler, T. W.

    AU - Grant, S. F.A.

    AU - Guo, Y.

    AU - Bergen, A. W.

    AU - Kaye, W.

    AU - Berrettini, W.

    AU - Hakonarson, H.

    AU - Herpertz-Dahlmann, B.

    AU - De Zwaan, M.

    AU - Herzog, W.

    AU - Ehrlich, S.

    AU - Zipfel, S.

    AU - Egberts, K. M.

    AU - Adan, R.

    AU - Brandys, M.

    AU - Van Elburg, A.

    AU - Boraska Perica, V.

    AU - Müller, T. D.

    AU - Tschöp, M. H.

    AU - Zeggini, E.

    AU - Bulik, C. M.

    AU - Collier, D.

    AU - Scherag, A.

    AU - Müller, T. D.

    AU - Hebebrand, J.

    AU - Perica, Vesna Boraska

    AU - Franklin, Christopher S.

    AU - Floyd, James A.B.

    AU - Thornton, Laura M.

    AU - Huckins, Laura M.

    AU - Southam, Lorraine

    AU - Rayner, N. William

    AU - Tachmazidou, Ioanna

    AU - Klump, Kelly L.

    AU - Treasure, Janet

    AU - Lewis, Cathryn M.

    AU - Schmidt, Ulrike

    AU - Tozzi, Federica

    AU - Iezebrink, Kirsty

    AU - Hebebrand, Johannes

    AU - Gorwood, Philip

    AU - Adan, Roger A.H.

    AU - Econs, M. J.

    AU - GCAN

    AU - WTCCC3

    AU - GIANT

    AU - EGG

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    AU - Children’s Hospital of Philadelphia/Price Foundation

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    N2 - The maintenance of normal body weight is disrupted in patients with anorexia nervosa (AN) for prolonged periods of time. Prior to the onset of AN, premorbid body mass index (BMI) spans the entire range from underweight to obese. After recovery, patients have reduced rates of overweight and obesity. As such, loci involved in body weight regulation may also be relevant for AN and vice versa. Our primary analysis comprised a cross-trait analysis of the 1000 single-nucleotide polymorphisms (SNPs) with the lowest P-values in a genome-wide association meta-analysis (GWAMA) of AN (GCAN) for evidence of association in the largest published GWAMA for BMI (GIANT). Subsequently we performed sex-stratified analyses for these 1000 SNPs. Functional ex vivo studies on four genes ensued. Lastly, a look-up of GWAMA-derived BMI-related loci was performed in the AN GWAMA. We detected significant associations (P-values <5 × 10-5, Bonferroni-corrected P<0.05) for nine SNP alleles at three independent loci. Interestingly, all AN susceptibility alleles were consistently associated with increased BMI. None of the genes (chr. 10: CTBP2, chr. 19: CCNE1, chr. 2: CARF and NBEAL1; the latter is a region with high linkage disequilibrium) nearest to these SNPs has previously been associated with AN or obesity. Sex-stratified analyses revealed that the strongest BMI signal originated predominantly from females (chr. 10 rs1561589; Poverall: 2.47 × 10-06/Pfemales: 3.45 × 10-07/Pmales: 0.043). Functional ex vivo studies in mice revealed reduced hypothalamic expression of Ctbp2 and Nbeal1 after fasting. Hypothalamic expression of Ctbp2 was increased in diet-induced obese (DIO) mice as compared with age-matched lean controls. We observed no evidence for associations for the look-up of BMI-related loci in the AN GWAMA. A cross-trait analysis of AN and BMI loci revealed variants at three chromosomal loci with potential joint impact. The chromosome 10 locus is particularly promising given that the association with obesity was primarily driven by females. In addition, the detected altered hypothalamic expression patterns of Ctbp2 and Nbeal1 as a result of fasting and DIO implicate these genes in weight regulation.

    AB - The maintenance of normal body weight is disrupted in patients with anorexia nervosa (AN) for prolonged periods of time. Prior to the onset of AN, premorbid body mass index (BMI) spans the entire range from underweight to obese. After recovery, patients have reduced rates of overweight and obesity. As such, loci involved in body weight regulation may also be relevant for AN and vice versa. Our primary analysis comprised a cross-trait analysis of the 1000 single-nucleotide polymorphisms (SNPs) with the lowest P-values in a genome-wide association meta-analysis (GWAMA) of AN (GCAN) for evidence of association in the largest published GWAMA for BMI (GIANT). Subsequently we performed sex-stratified analyses for these 1000 SNPs. Functional ex vivo studies on four genes ensued. Lastly, a look-up of GWAMA-derived BMI-related loci was performed in the AN GWAMA. We detected significant associations (P-values <5 × 10-5, Bonferroni-corrected P<0.05) for nine SNP alleles at three independent loci. Interestingly, all AN susceptibility alleles were consistently associated with increased BMI. None of the genes (chr. 10: CTBP2, chr. 19: CCNE1, chr. 2: CARF and NBEAL1; the latter is a region with high linkage disequilibrium) nearest to these SNPs has previously been associated with AN or obesity. Sex-stratified analyses revealed that the strongest BMI signal originated predominantly from females (chr. 10 rs1561589; Poverall: 2.47 × 10-06/Pfemales: 3.45 × 10-07/Pmales: 0.043). Functional ex vivo studies in mice revealed reduced hypothalamic expression of Ctbp2 and Nbeal1 after fasting. Hypothalamic expression of Ctbp2 was increased in diet-induced obese (DIO) mice as compared with age-matched lean controls. We observed no evidence for associations for the look-up of BMI-related loci in the AN GWAMA. A cross-trait analysis of AN and BMI loci revealed variants at three chromosomal loci with potential joint impact. The chromosome 10 locus is particularly promising given that the association with obesity was primarily driven by females. In addition, the detected altered hypothalamic expression patterns of Ctbp2 and Nbeal1 as a result of fasting and DIO implicate these genes in weight regulation.

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