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.
authors.affiliation: Department of Child and Adolescent Psychiatry, Psychotherapy, and Psychosomatics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Hinney
authors.affiliation: Clinical Epidemiology, Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Kesselmeier
authors.affiliation: Institute for Diabetes and Obesity, Helmholtz Diabetes Center & German Diabetes Center (DZD), Helmholtz Zentrum München, Neuherberg, Germany.|Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Jall
authors.affiliation: Department of Child and Adolescent Psychiatry, Psychotherapy, and Psychosomatics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: A-L
authors.initials: AL
authors.lastname: Volckmar
authors.affiliation: Department of Child and Adolescent Psychiatry, Psychotherapy, and Psychosomatics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Föcker
authors.affiliation: Department of Child and Adolescent Psychiatry, Psychotherapy, and Psychosomatics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Antel
authors.affiliation: Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.
authors.forename: I M
authors.initials: IM
authors.lastname: Heid
authors.affiliation: Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.
authors.forename: T W
authors.initials: TW
authors.lastname: Winkler
authors.affiliation: Department of Pediatrics, University of Pennsylvania, Philadelphia, PA, USA.|Divisions of Genetics and Endocrinology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.|The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: S F A
authors.initials: SF
authors.lastname: Grant
authors.affiliation: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Y
authors.identifier: 0000-0002-6549-8589
authors.initials: Y
authors.lastname: Guo
authors.affiliation: BioRealm, LLC, Culver City, CA, USA.
authors.forename: A W
authors.initials: AW
authors.lastname: Bergen
authors.affiliation: Department of Psychiatry, University of California, San Diego, San Diego, CA, USA.
authors.forename: W
authors.initials: W
authors.lastname: Kaye
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: W
authors.initials: W
authors.lastname: Berrettini
authors.affiliation: The Division of Human Genetics, Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Hakonarson
authors.affiliation: Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of the RWTH Aachen, Aachen, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Herpertz-Dahlmann
authors.affiliation: Department of Psychosomatic Medicine and Psychotherapy, Hannover Medical School, Hannover, Germany.
authors.forename: M
authors.initials: M
authors.lastname: de Zwaan
authors.affiliation: Department of Internal Medicine II, General Internal and Psychosomatic Medicine, University of Heidelberg, Heidelberg, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Herzog
authors.affiliation: Translational Developmental Neuroscience Section, Department of Child and Adolescent Psychiatry, Faculty of Medicine, TU-Dresden, University Hospital Carl Gustav Carus, Dresden University of Technology, Dresden, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Ehrlich
authors.affiliation: Department of Psychosomatic Medicine and Psychotherapy, Medical University Hospital, Tübingen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Zipfel
authors.affiliation: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany.
authors.forename: K M
authors.initials: KM
authors.lastname: Egberts
authors.affiliation: Brain Center Rudolf Magnus, Department of Translational Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.|Altrecht Eating Disorders Rintveld, Zeist, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Adan
authors.affiliation: Brain Center Rudolf Magnus, Department of Translational Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.|Altrecht Eating Disorders Rintveld, Zeist, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Brandys
authors.affiliation: Brain Center Rudolf Magnus, Department of Translational Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: van Elburg
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.|University of Split School of Medicine, Split, Croatia.
authors.forename: V
authors.initials: V
authors.lastname: Boraska Perica
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
authors.forename: C S
authors.initials: CS
authors.lastname: Franklin
authors.affiliation: Institute for Diabetes and Obesity, Helmholtz Diabetes Center & German Diabetes Center (DZD), Helmholtz Zentrum München, Neuherberg, Germany.|Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich, Germany.
authors.forename: M H
authors.initials: MH
authors.lastname: Tschöp
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
authors.forename: E
authors.initials: E
authors.lastname: Zeggini
authors.affiliation: Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|Department of Nutrition, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: C M
authors.initials: CM
authors.lastname: Bulik
authors.affiliation: Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK.|Eli Lilly and Company Ltd, Surrey, UK.
authors.forename: D
authors.initials: D
authors.lastname: Collier
authors.affiliation: Clinical Epidemiology, Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany.
authors.forename: A
authors.identifier: 0000-0002-9406-4704
authors.initials: A
authors.lastname: Scherag
authors.affiliation: Institute for Diabetes and Obesity, Helmholtz Diabetes Center & German Diabetes Center (DZD), Helmholtz Zentrum München, Neuherberg, Germany.|Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich, Germany.
authors.forename: T D
authors.initials: TD
authors.lastname: Müller
authors.affiliation: Department of Child and Adolescent Psychiatry, Psychotherapy, and Psychosomatics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Hebebrand
mesh_terms: D000483:Alleles; D000856:Anorexia Nervosa / Q000235:genetics*; D015992:Body Mass Index; D001835:Body Weight / Q000235:genetics; D030541:Databases, Genetic; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D009765:Obesity / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors