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; R Adan; M Brandys; A van Elburg; V Boraska Perica; C S Franklin; M H Tschöp; E Zeggini; C M Bulik; D Collier; A Scherag; T D Müller; J Hebebrand; GCAN; J.J. Hottenga; Gonneke Willemsen; D.I. Boomsma; C.E.M. van Beijsterveldt; C.M. Middeldorp; Eco  de Geus

doi:10.1038/mp.2016.71

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 EgbertsR Adan, M Brandys, A van Elburg, V Boraska Perica, C S Franklin, M H Tschöp, E Zeggini, C M Bulik, D Collier, A Scherag, T D Müller, J Hebebrand, GCAN, J.J. Hottenga, Gonneke Willemsen, D.I. Boomsma, C.E.M. van Beijsterveldt, C.M. Middeldorp, Eco de Geus

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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 language	English
Pages (from-to)	192-201
Number of pages	10
Journal	Molecular Psychiatry
Volume	22
Issue number	2
Early online date	17 May 2016
DOIs	https://doi.org/10.1038/mp.2016.71
Publication status	Published - Feb 2017

Funding

Funders	Funder number
Medical Research Council	MR/K013351/1, ES/J023299/1, MC_UU_12013/4
National Institute of Child Health and Human Development	R01HD056465

Keywords

Alleles
Anorexia Nervosa
Body Mass Index
Body Weight
Databases, Genetic
Female
Gene Frequency
Genetic Loci
Genetic Predisposition to Disease
Genetic Variation
Genome-Wide Association Study
Humans
Journal Article
Linkage Disequilibrium
Male
Obesity
Polymorphism, Single Nucleotide
Risk Factors

Cohort Studies

Netherlands Twin Register (NTR)

UN SDGs

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

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10.1038/mp.2016.71

Evidence for three genetic loci involved in both anorexia nervosa risk and variation of body mass indexFinal published version, 493 KBLicence: Article 25fa Dutch Copyright Act

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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., ... de Geus, E. (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

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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.",

keywords = "Alleles, Anorexia Nervosa, Body Mass Index, Body Weight, Databases, Genetic, Female, Gene Frequency, Genetic Loci, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Journal Article, Linkage Disequilibrium, Male, Obesity, Polymorphism, Single Nucleotide, Risk Factors",

author = "A Hinney and M Kesselmeier and S Jall and A-L Volckmar 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 Franklin, {C S} 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 GCAN and J.J. Hottenga and Gonneke Willemsen and D.I. Boomsma and {van Beijsterveldt}, C.E.M. and C.M. Middeldorp and {de Geus}, Eco",

year = "2017",

month = feb,

doi = "10.1038/mp.2016.71",

language = "English",

volume = "22",

pages = "192--201",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Springer Nature",

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Hinney, A, Kesselmeier, M, Jall, S, Volckmar, A-L, 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, Franklin, CS, Tschöp, MH, Zeggini, E, Bulik, CM, Collier, D, Scherag, A, Müller, TD, Hebebrand, J, GCAN, Hottenga, JJ, Willemsen, G, Boomsma, DI, van Beijsterveldt, CEM, Middeldorp, CM & de Geus, E 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

TY - JOUR

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 - Franklin, C S

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 - GCAN

AU - Hottenga, J.J.

AU - Willemsen, Gonneke

AU - Boomsma, D.I.

AU - van Beijsterveldt, C.E.M.

AU - Middeldorp, C.M.

AU - de Geus, Eco

PY - 2017/2

Y1 - 2017/2

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.

KW - Alleles

KW - Anorexia Nervosa

KW - Body Mass Index

KW - Body Weight

KW - Databases, Genetic

KW - Female

KW - Gene Frequency

KW - Genetic Loci

KW - Genetic Predisposition to Disease

KW - Genetic Variation

KW - Genome-Wide Association Study

KW - Humans

KW - Journal Article

KW - Linkage Disequilibrium

KW - Male

KW - Obesity

KW - Polymorphism, Single Nucleotide

KW - Risk Factors

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U2 - 10.1038/mp.2016.71

DO - 10.1038/mp.2016.71

M3 - Article

C2 - 27184124

SN - 1359-4184

VL - 22

SP - 192

EP - 201

JO - Molecular Psychiatry

JF - Molecular Psychiatry

IS - 2

ER -

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

Abstract

Funding

Keywords

Cohort Studies

UN SDGs

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