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.
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References
Cross-Disorder Group of the Psychiatric Genomics Consortium Smoller JW Craddock N Kendler K Lee PH Neale BM et al. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet 2013; 381: 1371–1379.
Serretti A, Fabbri C . Shared genetics among major psychiatric disorders. Lancet 2013; 381: 1339–1341.
Anderson CA, Boucher G, Lees CW, Franke A, D'Amato M, Taylor KD et al. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet 2011; 43: 246–252.
Gorwood P, Kipman A, Foulon C . The human genetics of anorexia nervosa. Eur J Pharmacol 2003; 480: 163–170.
Helder SG, Collier DA . The genetics of eating disorders. Curr Top Behav Neurosci 2011; 6: 157–175.
Thornton LM, Mazzeo SE, Bulik CM . The heritability of eating disorders: methods and current findings. Curr Top Behav Neurosci 2011; 6: 141–156.
Clarke TK, Weiss AR, Berrettini WH . The genetics of anorexia nervosa. Clin Pharmacol Ther 2012; 91: 181–188.
Treasure J, Zipfel S, Micali N, Wade T, Stice E, Claudino A et al. Anorexia nervosa. Nat Rev Dis Primers 2015; 1: 1–21.
Wang K, Zhang H, Bloss CS, Duvvuri V, Kaye W, Schork NJ et al. A genome-wide association study on common SNPs and rare CNVs in anorexia nervosa. Mol Psychiatry 2011; 16: 949–959.
Boraska V, Franklin CS, Floyd JA, Thornton LM, Huckins LM, Southam L et al. A genome-wide association study of anorexia nervosa. Mol Psychiatry 2014; 19: 1085–1094.
Maes HH, Neale MC, Eaves LJ . Genetic and environmental factors in relative body weight and human adiposity. Behav Genet 1997; 27: 325–351.
Hinney A, Vogel CI, Hebebrand J . From monogenic to polygenic obesity: recent advances. Eur Child Adolesc Psychiatry 2010; 19: 297–310.
Locke AE, Kahali B, Berndt SI, Justice AE, Pers TH, Day FR et al. Genetic studies of body mass index yield new insights for obesity biology. Nature 2015; 518: 197–206.
Willer CJ, Speliotes EK, Loos RJ, Li S, Lindgren CM, Heid IM et al. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat Genet 2009; 41: 25–34.
Walters RG, Jacquemont S, Valsesia A, de Smith AJ, Martinet D, Andersson J et al. A new highly penetrant form of obesity due to deletions on chromosome 16p11.2. Nature 2010; 463: 671–675.
Jacquemont S, Reymond A, Zufferey F, Harewood L, Walters RG, Kutalik Z et al. Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus. Nature 2011; 478: 97–102.
Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 1997; 88: 131–141.
Dempfle A, Hinney A, Heinzel-Gutenbrunner M, Raab M, Geller F, Gudermann T et al. Large quantitative effect of melanocortin-4 receptor gene mutations on body mass index. J Med Genet 2004; 41: 795–800.
Heid IM, Jackson AU, Randall JC, Winkler TW, Qi L, Steinthorsdottir V et al. Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. Nat Genet 2010; 42: 949–960.
Randall JC, Winkler TW, Kutalik Z, Berndt SI, Jackson AU, Monda KL et al. Anorexia nervosa viewed as an extreme weight condition: genetic implications. Hum Genet 1995; 95: 1–11.
Shungin D, Winkler TW, Croteau-Chonka DC, Ferreira T, Locke AE, Mägi R et al. New genetic loci link adipose and insulin biology to body fat distribution. Nature 2015; 518: 187–196.
Winkler TW, Justice AE, Graff M, Barata L, Feitosa MF, Chu S et al. The influence of age and sex on genetic associations with adult body size and shape: a large-scale genome-wide interaction study. PLoS Genet. 2015; 11: e1005378.
Hebebrand J, Remschmidt H . Anorexia nervosa viewed as an extreme weight condition: genetic implications. Hum Genet 1995; 95: 1–11.
Hinney A, Friedel S, Remschmidt H, Hebebrand J . Genetic risk factors in eating disorders. Am J Pharmacogenomics 2004; 4: 209–223.
Pinheiro AP, Sullivan PF, Bacaltchuck J, Prado-Lima PA, Bulik CM . Genetics in eating disorders: extending the boundaries of research. Rev Bras Psiquiatr 2006; 28: 218–225.
Sulek S, Lacinová Z, Dolinková M, Haluzik M . Genetic polymorphisms as a risk factor for anorexia nervosa. Prague Med Rep 2007; 108: 215–225.
Day J, Ternouth A, Collier DA . Eating disorders and obesity: two sides of the same coin? Epidemiol Psichiatr Soc 2009; 18: 96–100.
Scherag A, Dina C, Hinney A, Vatin V, Scherag S, Vogel CI et al. Two new loci for body-weight regulation identified in a joint analysis of genome-wide association studies for early-onset extreme obesity in French and German study groups. PLoS Genet 2010; 6: e1000916.
Gervasini G, Gamero-Villarroel C . Discussing the putative role of obesity-associated genes in the etiopathogenesis of eating disorders. Pharmacogenomics 2015; 16: 1287–1305.
Bulik-Sullivan B, Finucane HK, Anttila V, Gusev A, Day FR et al, ReproGen Consortium, Psychiatric Genomics Consortium. An atlas of genetic correlations across human diseases and traits. Nat Genet 2015; 47: 1236–1241.
Fall T, Ingelsson E . Genome-wide association studies of obesity and metabolic syndrome. Mol Cell Endocrinol 2014; 382: 740–757.
Guo Y, Lanktree MB, Taylor KC, Hakonarson H, Lange LA, Keating BJ et al. Gene-centric meta-analyses of 108 912 individuals confirm known body mass index loci and reveal three novel signals. Hum Mol Genet 2013; 22: 184–201.
Coners H, Remschmidt H, Hebebrand J . The relationship between premorbid body weight, weight loss, and weight at referral in adolescent patients with anorexia nervosa. Int J Eat Disord 1999; 26: 171–178.
Föcker M, Bühren K, Timmesfeld N, Dempfle A, Knoll S, Schwarte R et al. The relationship between premorbid body weight and weight at referral, at discharge and at 1-year follow-up in anorexia nervosa. Eur Child Adolesc Psychiatry 2015; 24: 537–544.
Hebebrand J . Identification of determinants of referral and follow-up body mass index of adolescent patients with anorexia nervosa: evidence for the role of premorbid body weight. Eur Child Adolesc Psychiatry 2015; 24: 471–475.
Hebebrand J, Himmelmann GW, Herzog W, Herpertz-Dahlmann BM, Steinhausen HC, Amstein M et al. Prediction of low body weight at long-term follow-up in acute anorexia nervosa by low body weight at referral. Am J Psychiatry 1997; 154: 566–569.
Keski-Rahkonen A, Raevuori A, Bulik CM, Hoek HW, Rissanen A, Kaprio J . Factors associated with recovery from anorexia nervosa: a population-based study. Int J Eat Disord 2014; 47: 117–123.
Steinhausen HC, Jensen CM . Time trends in lifetime incidence rates of first-time diagnosed anorexia nervosa and bulimia nervosa across 16 years in a Danish nationwide psychiatric registry study. Int J Eat Disord 2015; 48: 845–850.
Knoll S, Föcker M, Hebebrand J . Clinical problems encountered in the treatment of adolescents with anorexia nervosa. Z Kinder Jugendpsychiatr Psychother 2013; 41: 433–446.
Bradfield JP, Taal HR, Timpson NJ, Scherag A, Lecoeur C, Warrington NM et al. A genome-wide association meta-analysis identifies new childhood obesity loci. Nat Genet 2012; 44: 526–531.
Yazdi FT, Clee SM, Meyre D . Obesity genetics in mouse and human: back and forth, and back again. PeerJ 2015; 3: e856.
Comuzzie AG, Cole SA, Laston SL, Voruganti VS, Haack K, Gibbs RA et al. Novel genetic loci identified for the pathophysiology of childhood obesity in the Hispanic population. PLoS One 2012; 7: e51954.
Müller TD, Müller A, Yi CX, Habegger KM, Meyer CW, Gaylinn BD et al. The orphan receptor Gpr83 regulates systemic energy metabolism via ghrelin-dependent and ghrelin-independent mechanisms. Nat Commun 2013; 4: 1968.
Müller TD, Föcker M, Holtkamp K, Herpertz-Dahlmann B, Hebebrand J . Leptin-mediated neuroendocrine alterations in anorexia nervosa: somatic and behavioral implications. Child Adolesc Psychiatr Clin N Am 2009; 18: 117–129.
Hebebrand J, Müller TD, Holtkamp K, Herpertz-Dahlmann B . The role of leptin in anorexia nervosa: clinical implications. Mol Psychiatry 2007; 12: 23–35.
Müller TD, Nogueiras R, Andermann ML, Andrews ZB, Anker SD, Argente J et al. Ghrelin. Mol Metab 2015; 4: 437–460.
Tong M, Brugeaud A, Edge AS . Regenerated synapses between postnatal hair cells and auditory neurons. J Assoc Res Otolaryngol 2013; 14: 321–329.
Shieh PB, Hu SC, Bobb K, Timmusk T, Ghosh A . Identification of a signaling pathway involved in calcium regulation of BDNF expression. Neuron 1998; 20: 727–740.
Shieh PB, Ghosh A . Molecular mechanisms underlying activity-dependent regulation of BDNF expression. J Neurobiol 1999; 41: 127–134.
Finkbeiner S . Calcium regulation of the brain-derived neurotrophic factor gene. Cell Mol Life Sci 2000; 57: 394–401.
Xia Z, Storm DR . CaRF: a neuronal transcription factor that CaREs. Neuron 2002; 33: 315–316.
Tao X, West AE, Chen WG, Corfas G, Greenberg ME . A calcium-responsive transcription factor, CaRF, that regulates neuronal activity-dependent expression of BDNF. Neuron 2002; 33: 383–395.
Williams EJ, Walsh FS, Doherty P . The FGF receptor uses the endocannabinoid signaling system to couple to an axonal growth response. J Cell Biol 2003; 160: 481–486.
Merighi A, Bardoni R, Salio C, Lossi L, Ferrini F, Prandini M et al. Presynaptic functional trkB receptors mediate the release of excitatory neurotransmitters from primary afferent terminals in lamina II (substantia gelatinosa) of postnatal rat spinal cord. Dev Neurobiol 2008; 68: 457–475.
Singer W, Panford-Walsh R, Watermann D, Hendrich O, Zimmermann U, Köpschall I et al. Salicylate alters the expression of calcium response transcription factor 1 in the cochlea: implications for brain-derived neurotrophic factor transcriptional regulation. Mol Pharmacol 2008; 73: 1085–1091.
McDowell KA, Hutchinson AN, Wong-Goodrich SJ, Presby MM, Su D, Rodriguiz RM et al. Reduced cortical BDNF expression and aberrant memory in Carf knock-out mice. J Neurosci 2010; 30: 7453–7465.
Pfenning AR, Kim TK, Spotts JM, Hemberg M, Su D, West AE . Genome-wide identification of calcium-response factor (CaRF) binding sites predicts a role in regulation of neuronal signaling pathways. PLoS One 2010; 5: e10870.
Alboni S, Benatti C, Capone G, Corsini D, Caggia F, Tascedda F et al. Time-dependent effects of escitalopram on brain derived neurotrophic factor (BDNF) and neuroplasticity related targets in the central nervous system of rats. Eur J Pharmacol 2010; 643: 180–187.
West AE . Biological functions and transcriptional targets of CaRF in neurons. Cell Calcium 2011; 49: 290–295.
Lyons MR, Schwarz CM, West AE . Members of the myocyte enhancer factor 2 transcription factor family differentially regulate Bdnf transcription in response to neuronal depolarization. J Neurosci 2012; 32: 12780–12785.
Calabrese F, Guidotti G, Middelman A, Racagni G, Homberg J, Riva MA . Lack of serotonin transporter alters BDNF expression in the rat brain during early postnatal development. Mol Neurobiol 2013; 48: 244–256.
Calabrese F, Guidotti G, Racagni G, Riva MA . Reduced neuroplasticity in aged rats: a role for the neurotrophin brain-derived neurotrophic factor. Neurobiol Aging 2013; 34: 2768–2776.
Ji JF, Ji SJ, Sun R, Li K, Zhang Y, Zhang LY et al. Forced running exercise attenuates hippocampal neurogenesis impairment and the neurocognitive deficits induced by whole-brain irradiation via the BDNF-mediated pathway. Biochem Biophys Res Commun 2014; 443: 646–651.
Hinney A, Volckmar AL, Antel J . Genes and the hypothalamic control of metabolism in humans. Best Pract Res Clin Endocrinol Metab 2014; 28: 635–647.
Speliotes EK, Willer CJ, Berndt SI, Monda KL, Thorleifsson G, Jackson AU et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet 2010; 42: 937–948.
Pelleymounter MA, Cullen MJ, Wellman CL . Characteristics of BDNF-induced weight loss. Exp Neurol 1995; 131: 229–238.
Bariohay B, Lebrun B, Moyse E, Jean A . Brain-derived neurotrophic factor plays a role as an anorexigenic factor in the dorsal vagal complex. Endocrinology 2005; 146: 5612–5620.
Gotoh K, Masaki T, Chiba S, Ando H, Fujiwara K, Shimasaki T et al. Brain-derived neurotrophic factor, corticotropin-releasing factor, and hypothalamic neuronal histamine interact to regulate feeding behavior. J Neurochem 2013; 125: 588–598.
Gelegen C, van den Heuvel J, Collier DA, Campbell IC, Oppelaar H, Hessel E et al. Dopaminergic and brain-derived neurotrophic factor signalling in inbred mice exposed to a restricted feeding schedule. Genes Brain Behav 2008; 7: 552–559.
Charrier C, Chigr F, Tardivel C, Mahaut S, Jean A, Najimi M et al. BDNF regulation in the rat dorsal vagal complex during stress-induced anorexia. Brain Res 2006; 1107: 52–57.
An JJ, Liao GY, Kinney CE, Sahibzada N, Xu B . Discrete BDNF neurons in the paraventricular hypothalamus control feeding and energy expenditure. Cell Metab 2015; 22: 175–188.
Ribasés M, Gratacòs M, Armengol L, de Cid R, Badía A, Jiménez L et al. dMet66 in the brain-derived neurotrophic factor (BDNF) precursor is associated with anorexia nervosa restrictive type. Mol Psychiatry 2003; 8: 745–751.
Ribasés M, Gratacòs M, Fernández-Aranda F, Bellodi L, Boni C, Anderluh M et al. Association of BDNF with anorexia, bulimia and age of onset of weight loss in six European populations. Hum Mol Genet 2004; 13: 1205–1212.
Ribasés M, Gratacòs M, Fernández-Aranda F, Bellodi L, Boni C, Anderluh M et al. Association of BDNF with restricting anorexia nervosa and minimum body mass index: a family-based association study of eight European populations. Eur J Hum Genet 2005; 13: 428–434.
de Krom M, Bakker SC, Hendriks J, van Elburg A, Hoogendoorn M, Verduijn W et al. Polymorphisms in the brain-derived neurotrophic factor gene are not associated with either anorexia nervosa or schizophrenia in Dutch patients. Psychiatr Genet 2005; 15: 81.
Friedel S, Horro FF, Wermter AK, Geller F, Dempfle A, Reichwald K et al. Mutation screen of the brain derived neurotrophic factor gene (BDNF): identification of several genetic variants and association studies in patients with obesity, eating disorders, and attention-deficit/hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet 2005; 132B: 96–99.
Dardennes RM, Zizzari P, Tolle V, Foulon C, Kipman A, Romo L et al. Family trios analysis of common polymorphisms in the obestatin/ghrelin, BDNF and AGRP genes in patients with Anorexia nervosa: association with subtype, body-mass index, severity and age of onset. Psychoneuroendocrinology 2007; 32: 106–113.
Rybakowski F, Dmitrzak-Weglarz M, Szczepankiewicz A, Skibinska M, Slopien A, Rajewski A et al. Brain derived neurotrophic factor gene Val66Met and -270C/T polymorphisms and personality traits predisposing to anorexia nervosa. Neuro Endocrinol Lett 2007; 28: 153–158.
Dmitrzak-Weglarz M, Skibinska M, Slopien A, Szczepankiewicz A, Rybakowski F, Kramer L et al. BDNF Met66 allele is associated with anorexia nervosa in the Polish population. Psychiatr Genet 2007; 17: 245–246.
Slof-Op 't Landt MC, Meulenbelt I, Bartels M, Suchiman E, Middeldorp CM, Houwing-Duistermaat JJ et al. Association study in eating disorders: TPH2 associates with anorexia nervosa and self-induced vomiting. Genes Brain Behav 2011; 10: 236–243.
Ando T, Ishikawa T, Hotta M, Naruo T, Okabe K, Nakahara T et al. No association of brain-derived neurotrophic factor Val66Met polymorphism with anorexia nervosa in Japanese. Am J Med Genet B Neuropsychiatr Genet 2012; 159B: 48–52.
Brandys MK, Kas MJ, van Elburg AA, Ophoff R, Slof-Op't Landt MC, Middeldorp CM et al. The Val66Met polymorphism of the BDNF gene in anorexia nervosa: new data and a meta-analysis. World J Biol Psychiatry 2013; 14: 441–451.
Pjetri E, Dempster E, Collier DA, Treasure J, Kas MJ, Mill J et al. Quantitative promoter DNA methylation analysis of four candidate genes in anorexia nervosa: a pilot study. J Psychiatr Res 2013; 47: 280–282.
Gamero-Villarroel C, Gordillo I, Carrillo JA, García-Herráiz A, Flores I, Jiménez M et al. BDNF genetic variability modulates psychopathological symptoms in patients with eating disorders. Eur Child Adolesc Psychiatry 2014; 23: 669–679.
Nakazato M, Hashimoto K, Shimizu E, Kumakiri C, Koizumi H, Okamura N et al. Decreased levels of serum brain-derived neurotrophic factor in female patients with eating disorders. Biol Psychiatry 2003; 54: 485–490.
Nakazato M, Hashimoto K, Yoshimura K, Hashimoto T, Shimizu E, Iyo M . No change between the serum brain-derived neurotrophic factor in female patients with anorexia nervosa before and after partial weight recovery. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30: 1117–1121.
Nakazato M, Tchanturia K, Schmidt U, Campbell IC, Treasure J, Collier DA et al. Brain-derived neurotrophic factor (BDNF) and set-shifting in currently ill and recovered anorexia nervosa (AN) patients. Psychol Med 2009; 39: 1029–1035.
Nakazato M, Hashimoto K, Shimizu E, Niitsu T, Iyo M . Possible involvement of brain-derived neurotrophic factor in eating disorders. IUBMB Life 2012; 64: 355–361.
Monteleone P, Tortorella A, Martiadis V, Serritella C, Fuschino A, Maj M . Opposite changes in the serum brain-derived neurotrophic factor in anorexia nervosa and obesity. Psychosom Med 2004; 66: 744–748.
Monteleone P, Fabrazzo M, Martiadis V, Serritella C, Pannuto M, Maj M . Circulating brain-derived neurotrophic factor is decreased in women with anorexia and bulimia nervosa but not in women with binge-eating disorder: relationships to co-morbid depression, psychopathology and hormonal variables. Psychol Med 2005; 35: 897–905.
Monteleone P, Maj M . Dysfunctions of leptin, ghrelin, BDNF and endocannabinoids in eating disorders: beyond the homeostatic control of food intake. Psychoneuroendocrinology 2013; 38: 312–330.
Mercader JM, Fernández-Aranda F, Gratacòs M, Ribasés M, Badía A, Villarejo C et al. Blood levels of brain-derived neurotrophic factor correlate with several psychopathological symptoms in anorexia nervosa patients. Neuropsychobiology 2007; 56: 185–190.
Mercader JM, Ribasés M, Gratacòs M, González JR, Bayés M, de Cid R et al. Altered brain-derived neurotrophic factor blood levels and gene variability are associated with anorexia and bulimia. Genes Brain Behav 2007; 6: 706–716.
Mercader JM, Fernández-Aranda F, Gratacòs M, Aguera Z, Forcano L, Ribasés M et al. Correlation of BDNF blood levels with interoceptive awareness and maturity fears in anorexia and bulimia nervosa patients. J Neural Transm 2010; 117: 505–512.
Ehrlich S, Salbach-Andrae H, Eckart S, Merle JV, Burghardt R, Pfeiffer E et al. Serum brain-derived neurotrophic factor and peripheral indicators of the serotonin system in underweight and weight-recovered adolescent girls and women with anorexia nervosa. J Psychiatry Neurosci 2009; 34: 323–329.
Saito S, Watanabe K, Hashimoto E, Saito T . Low serum BDNF and food intake regulation: a possible new explanation of the pathophysiology of eating disorders. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33: 312–316.
Brandys MK, Kas MJ, van Elburg AA, Campbell IC, Adan RA . A meta-analysis of circulating BDNF concentrations in anorexia nervosa. World J Biol Psychiatry 2011; 12: 444–454.
Dmitrzak-Weglarz M, Skibinska M, Slopien A, Tyszkiewicz M, Pawlak J, Maciukiewicz M et al. Serum neurotrophin concentrations in polish adolescent girls with anorexia nervosa. Neuropsychobiology 2013; 67: 25–32.
Zwipp J, Hass J, Schober I, Geisler D, Ritschel F, Seidel M et al. Serum brain-derived neurotrophic factor and cognitive functioning in underweight, weight-recovered and partially weight-recovered females with anorexia nervosa. Prog Neuropsychopharmacol Biol Psychiatry 2014; 54: 163–169.
Eddy KT, Lawson EA, Meade C, Meenaghan E, Horton SE, Misra M et al. Appetite regulatory hormones in women with anorexia nervosa: binge-eating/purging versus restricting type. J Clin Psychiatry 2015; 76: 19–24.
Rask-Andersen M, Olszewski PK, Levine AS, Schiöth HB . Molecular mechanisms underlying anorexia nervosa: focus on human gene association studies and systems controlling food intake. Brain Res Rev 2010; 62: 147–164.
Rosas-Vargas H, Martínez-Ezquerro JD, Bienvenu T . Brain-derived neurotrophic factor, food intake regulation, and obesity. Arch Med Res 2011; 42: 482–494.
Banke E, Rödström K, Ekelund M, Dalla-Riva J, Lagerstedt JO, Nilsson S et al. Superantigen activates the gp130 receptor on adipocytes resulting in altered adipocyte metabolism. Metabolism 2014; 63: 831–840.
Chornokur G, Amankwah EK, Davis SN, Phelan CM, Park JY, Pow-Sang J et al. Variation in HNF1B and obesity may influence prostate cancer risk in African American men: a pilot study. Prostate Cancer 2013; 2013: 384594.
Guirguis E, Hockman S, Chung YW, Ahmad F, Gavrilova O, Raghavachari N et al. A role for phosphodiesterase 3B in acquisition of brown fat characteristics by white adipose tissue in male mice. Endocrinology 2013; 154: 3152–3167.
Vernochet C, Peres SB, Davis KE, McDonald ME, Qiang L, Wang H et al. C/EBPalpha and the corepressors CtBP1 and CtBP2 regulate repression of select visceral white adipose genes during induction of the brown phenotype in white adipocytes by peroxisome proliferator-activated receptor gamma agonists. Mol Cell Biol 2009; 29: 4714–4728.
Vernochet C, Davis KE, Scherer PE, Farmer SR . Mechanisms regulating repression of haptoglobin production by peroxisome proliferator-activated receptor-gamma ligands in adipocytes. Endocrinology 2010; 151: 586–594.
Farmer SR . Molecular determinants of brown adipocyte formation and function. Genes Dev 2008; 22: 1269–1275.
Kajimura S, Seale P, Tomaru T, Erdjument-Bromage H, Cooper MP, Ruas JL et al. Regulation of the brown and white fat gene programs through a PRDM16/CtBP transcriptional complex. Genes Dev 2008; 22: 1397–1409.
Hildebrand JD, Soriano P . Overlapping and unique roles for C-terminal binding protein 1 (CtBP1) and CtBP2 during mouse development. Mol Cell Biol 2002; 22: 5296–5307.
Wang L, Xu L, Xu M, Liu G, Xing J, Sun C et al. Obesity-associated MiR-342-3p promotes adipogenesis of mesenchymal stem cells by suppressing CtBP2 and releasing C/EBPα from CtBP2 binding. Cell Physiol Biochem 2015; 35: 2285–2298.
Li Y, Yang XH, Fang SJ, Qin CF, Sun RL, Liu ZY et al. HOXA7 stimulates human hepatocellular carcinoma proliferation through cyclin E1/CDK2. Oncol Rep 2015; 33: 990–996.
Zhu HJ, Pan H, Zhang XZ, Li NS, Wang LJ, Yang HB et al. The effect of myostatin on the proliferation and lipid accumulation in 3T3-L1 preadipocytes. J Mol Endocrinol 2015; 54: 217–226.
Hadano S, Hand CK, Osuga H, Yanagisawa Y, Otomo A, Devon RS et al. A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nat Genet 2001; 29: 166–173.
Acknowledgements
We express our gratitude to all participants. We thank the following sources for funding or research: the German Ministry for Education and Research (National Genome Research Net-Plus 01GS0820 and 01KU0903; AS, MK and the CSCC were supported by 01EO1002, 01EO1502), the German Research Foundation (DFG; HI865/2-1, SFB940/1, SCHE1648/1-3, TS226/3-1), the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 245009 and no. 262055, and the National Institutes of Health (NIH; R01DK075787), funding to MHT from the Alexander von Humboldt Foundation, the Helmholtz Alliance ICEMED—Imaging and Curing Environmental Metabolic Diseases, through the Initiative and Networking Fund of the Helmholtz Association, the Helmholtz cross-program topic 'Metabolic Dysfunction.' the WTCCC3 WT088827/Z/09 entitled 'A genome-wide association study of anorexia nervosa.' We would like to thank the Exome Aggregation Consortium and the groups that provided exome variant data for comparison. A full list of contributing groups can be found at http://exac.broadinstitute.org/about. AH was supported by the ‘Landesprogramm für Geschlechtergerechte Hochschulen - Programmstrang Förderung von Denominationen in der Genderforschung.' The Children’s Hospital of Philadelphia/Price Foundation gratefully thank all the patients and their families who were enrolled in this study, as well as all the control subjects who donated blood samples to Children's Hospital of Philadelphia (CHOP) for genetic research purposes. We thank the Price Foundation for their support of the Collaborative Group effort that was responsible for recruitment of patients, collection of clinical information and provision of the DNA samples used in this study. We also thank the Klarman Family Foundation for supporting the study. We thank the technical staff at the Center for Applied Genomics at CHOP for producing the genotypes used for analyses and the nursing, medical assistant and medical staff for their invaluable help with sample recruitments. CTB and NJS are funded in part by the Scripps Translational Sciences Institute Clinical Translational Science Award (Grant Number U54 RR0252204-01). All genome-wide genotyping was funded by an Institute Development Award to the Center for Applied Genomics from the CHOP. 2011–2014 Davis Foundation Postdoctoral Fellowship Program in Eating Disorders Research Award to YG and the 2012–2015 Davis Foundation Postdoctoral Fellowship Program in Eating Disorders Research Award to DL.
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CMB is a grant recipient from Shire Pharmaceuticals, and none of the other authors declared.
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GENETIC CONSORTIUM FOR ANOREXIA NERVOSA (GCAN) Vesna Boraska Perica, Christopher S Franklin, James AB 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 AH Adan, Martien JH Kas, Angela Favaro, Paolo Santonastaso, Fernando Fernández-Aranda, Monica Gratacos, Filip Rybakowski, Monika Dmitrzak-Weglarz, Jaakko Kaprio, Anna Keski-Rahkonen, Anu Raevuori-Helkamaa, Eric F Van Furth, Margarita CT Slof-Op’t Landt, James I Hudson, Ted Reichborn-Kjennerud, Gun Peggy S Knudsen, Palmiero Monteleone, Allan S Kaplan, Andreas Karwautz, Hakon Hakonarson, Wade H Berrettini, Yiran Guo, Dong Li, Nicholas J Schork, Gen Komaki, Tetsuya Ando, Hidetoshi Inoko, Tõnu Esko, Krista Fischer, Katrin Männik, Andres Metspalu, Jessica H Baker, Roger D Cone, Jennifer Dackor, Janiece E DeSocio, Christopher E Hilliard, Julie K O'Toole, Jacques Pantel, Jin P Szatkiewicz, Chrysecolla Taico, Stephanie Zerwas, Sara E Trace, Oliver S P Davis, Sietske Helder, Katharina Bühren, Roland Burghardt, Martina de Zwaan, Karin Egberts, Stefan Ehrlich, Beate Herpertz-Dahlmann, Wolfgang Herzog, Hartmut Imgart, André Scherag, Susann Scherag, Stephan Zipfel, Claudette Boni, Nicolas Ramoz, Audrey Versini, Marek K Brandys, Unna N Danner, Carolien de Kove, Judith Hendriks, Bobby P C Koeleman, Roel A Ophoff, Eric Strengman, Annemarie A van Elburg, Alice Bruson, Maurizio Clementi, Daniela Degortes, Monica Forzan, Elena Tenconi, Elisa Docampo, Geòrgia Escaramí Susana Jiménez-Murcia, Jolanta Lissowska, Andrzej Rajewski, Neonila Szeszenia-Dabrowska, Agnieszka Slopien, Joanna Hauser, Leila Karhunen, Ingrid Meulenbelt, P Eline Slagboom, Alfonso Tortorella, Mario Maj, George Dedoussis, Dimitris Dikeos, Fragiskos Gonidakis, Konstantinos Tziouvas, Artemis Tsitsika, Hana Papezova, Lenka Slachtova, Debora Martaskova, James L Kennedy, Robert D Levitan, Zeynep Yilmaz, Julia Huemer, Doris Koubek, Elisabeth Merl, Gudrun Wagner, Paul Lichtenstein, Gerome Breen, Sarah Cohen-Woods, Anne Farmer, Peter McGuffin, Sven Cichon, Ina Giegling, Stefan Herms, Dan Rujescu, Stefan Schreiber, H-Erich Wichmann, Christian Dina, Rob Sladek, Giovanni Gambaro, Nicole Soranzo, Antonio Julia, Sara Marsal, Raquel Rabionet, Valerie Gaborieau, Danielle M Dick, Aarno Palotie, Samuli Ripatti, Elisabeth Widén, Ole A Andreassen, Thomas Espeseth, Astri Lundervold, Ivar Reinvang, Vidar M Steen, Stephanie Le Hellard, Morten Mattingsdal, Ioanna Ntalla, Vladimir Bencko, Lenka Foretova, Vladimir Janout, Marie Navratilova, Steven Gallinger, Dalila Pinto, Stephen W Scherer, Harald Aschauer, Laura Carlberg, Alexandra Schosser, Lars Alfredsson, Bo Ding, Lars Klareskog, Leonid Padyukov, Chris Finan, Gursharan Kalsi, Marion Roberts, Darren W Logan, Leena Peltonen, Graham R S Ritchie, Jeff C Barrett, Xavier Estivill, Anke Hinney, Patrick F Sullivan, David A Collier, Eleftheria Zeggini, and Cynthia M Bulik.
WELLCOME TRUST CASE CONTROL CONSORTIUM 3 (WTCCC3) Carl A Anderson, Jeffrey C Barrett, James AB Floyd, Christopher S Franklin, Ralph McGinnis, Nicole Soranzo, Eleftheria Zeggini, Jennifer Sambrook, Jonathan Stephens, Willem H Ouwehand, Wendy L McArdle, Susan M Ring, David P Strachan, Graeme Alexander, Cynthia M Bulik, David A Collier, Peter J Conlon, Anna Dominiczak, Audrey Duncanson, Adrian Hill, Cordelia Langford, Graham Lord, Alexander P Maxwell, Linda Morgan, Leena Peltonen, Richard N Sandford, Neil Sheerin, Frederik O Vannberg, Hannah Blackburn, Wei-Min Chen, Sarah Edkins, Mathew Gillman, Emma Gray, Sarah E Hunt, Suna Nengut-Gumuscu, Simon Potter, Stephen S Rich, Douglas Simpkin, and Pamela Whittaker.
GENETIC INVESTIGATION OF ANTHROPOMETRIC TRAITS CONSORTIUM (GIANT) de Bakker P, Bültmann U, Geleijnse M, Harst Pv, Koppelman G, Rosmalen JG, van Rossum L, Smidt H, Swertz MA, Stolk RP, Alizadeh B, de Boer R, Boezen HM, Bruinenberg M, Franke L, van der Harst P, Hillege H, van der Klauw M, Navis G, Ormel J, Postma D, Rosmalen J, Slaets J, Snieder H, Stolk R, Wolffenbuttel B, Wijmenga C, Berg J, Blackwood D, Campbell H, Cavanagh J, Connell J, Connor M, Cunningham-Burley S, Deary I, Dominiczak A, Ellis P, FitzPatrick B, Ford I, Gertz R, Grau A, Haddow G, Jackson C, Kerr S, Lindsay R, McGilchrist M, McIntyre D, Morris A, Morton R, Muir W, Murray G, Palmer C, Pell J, Philp A, Porteous D, Porteous M, Procter R, Ralston S, Reid D, Sinnott R, Smith B, Clair DS, Sullivan F, Sweetland M, Ure J, Watt G, Wolf R, Wright A, Berndt SI, Gustafsson S, Mägi R, Ganna A, Wheeler E, Feitosa MF, Justice AE, Monda KL, Croteau- Chonka DC, Day FR, Esko T, Fall T, Ferreira T, Gentilini D, Jackson AU, Luan J, Randall JC, Vedantam S, Willer CJ, Winkler TW, Wood AR, Workalemahu T, Hu YJ, Lee SH, Liang L, Lin DY, Min JL, Neale BM, Thorleifsson G, Yang J, Albrecht E, Amin N, Bragg-Gresham JL, Cadby G, den Heijer M, Eklund N, Fischer K, Goel A, Hottenga JJ, Huffman JE, Jarick I, Johansson A, Johnson T, Kanoni S, Kleber ME, König IR, Kristiansson K, Kutalik Z, Lamina C, Lecoeur C, Li G, Mangino M, McArdle WL, Medina-Gomez C, Müller-Nurasyid M, Ngwa JS, Nolte IM, Paternoster L, Pechlivanis S, Perola M, Peters MJ, Preuss M, Rose LM, Shi J, Shungin D, Smith AV, Strawbridge RJ, Surakka I, Teumer A, Trip MD, Tyrer J, Van Vliet- Ostaptchouk JV, Vandenput L, Waite LL, Zhao JH, Absher D, Asselbergs FW, Atalay M, Attwood AP, Balmforth AJ, Basart H, Beilby J, Bonnycastle LL, Brambilla P, Bruinenberg M, Campbell H, Chasman DI, Chines PS, Collins FS, Connell JM, Cookson W, de Faire U, de Vegt F, Dei M, Dimitriou M, Edkins S, Estrada K, Evans DM, Farrall M, Ferrario MM, Ferrières J, Franke L, Frau F, Gejman PV, Grallert H, Grönberg H, Gudnason V, Hall AS, Hall P, Hartikainen AL, Hayward C, Heard-Costa NL, Heath AC, Hebebrand J, Homuth G, Hu FB, Hunt SE, Hyppönen E, Iribarren C, Jacobs KB, Jansson JO, Jula A, Kähönen M, Kathiresan S, Kee F, Khaw KT, Kivimaki M, Koenig W, Kraja AT, Kumari M, Kuulasmaa K, Kuusisto J, Laitinen JH, Lakka TA, Langenberg C, Launer LJ, Lind L, Lindström J, Liu J, Liuzzi A, Lokki ML, Lorentzon M, Madden PA, Magnusson PK, Manunta P, Marek D, März W, Mateo Leach I, McKnight B, Medland SE, Mihailov E, Milani L, Montgomery GW, Mooser V, Mühleisen TW, Munroe PB, Musk AW, Narisu N, Navis G, Nicholson G, Nohr EA, Ong KK, Oostra BA, Palmer CN, Palotie A, Peden JF, Pedersen N, Peters A, Polasek O, Pouta A, Pramstaller PP, Prokopenko I, Pütter C, Radhakrishnan A, Raitakari O, Rendon A, Rivadeneira F, Rudan I, Saaristo TE, Sambrook JG, Sanders AR, Sanna S, Saramies J, Schipf S, Schreiber S, Schunkert H, Shin SY, Signorini S, Sinisalo J, Skrobek B, Soranzo N, Stancakova A, Stark K, Stephens JC, Stirrups K, Stolk RP, Stumvoll M, Swift AJ, Theodoraki EV, Thorand B, Tregouet DA, Tremoli E, Van der Klauw MM, van Meurs JB, Vermeulen SH, Viikari J, Virtamo J, Vitart V, Waeber G, Wang Z, Widen E, Wild SH, Willemsen G, Winkelmann BR, Witteman JC, Wolffenbuttel BH, Wong A, Wright AF, Zillikens M, Amouyel P, Boehm BO, Boerwinkle E, Boomsma DI, Caulfield MJ, Chanock SJ, Cupples L, Cusi D, Dedoussis GV, Erdmann J, Eriksson JG, Franks PW, Froguel P, Gieger C, Gyllensten U, Hamsten A, Harris TB, Hengstenberg C, Hicks AA, Hingorani A, Hinney A, Hofman A, Hovingh KG, Hveem K, Illig T, Jarvelin MR, Jöckel KH, Keinanen-Kiukaanniemi SM, Kiemeney LA, Kuh D, Laakso M, Lehtimäki T, Levinson DF, Martin NG, Metspalu A, Morris AD, Nieminen MS, Njølstad I, Ohlsson C, Oldehinkel AJ, Ouwehand WH, Palmer LJ, Penninx B, Power C, Province MA, Psaty BM, Qi L, Rauramaa R, Ridker PM, Ripatti S, Salomaa V, Samani NJ, Snieder H, Sørensen TI, Spector TD, Stefansson K, Tönjes A, Tuomilehto J, Uitterlinden AG, Uusitupa M, van der Harst P, Vollenweider P, Wallaschofski H, Wareham NJ, Watkins H, Wichmann H-, Wilson JF, Abecasis GR, Assimes TL, Barroso I, Boehnke M, Borecki IB, Deloukas P, Fox CS, Frayling T, Groop LC, Haritunian T, Heid IM, Hunter D, Kaplan RC, Karpe F, Moffatt M, Mohlke KL, O'Connell JR, Pawitan Y, Schadt EE, Schlessinger D, Steinthorsdottir V, Strachan DP, Thorsteinsdottir U, van Duijn CM, Visscher PM, Di Blasio AM, Hirschhorn JN, Lindgren CM, Morris AP, Meyre D, Scherag A, McCarthy MI, Speliotes EK, North KE, Loos RJ, Ingelsson E.
EARLY GROWTH GENETICS CONSORTIUM (EGG) Adair LS, Ang W, Atalay M, van Beijsterveldt T, Bergen N, Benke K, Berry DJ, Boomsma DI, Bradfield JP, Charoen P, Coin L, Cooper C, Cousminer DL, Das S, Davis OS, Dedoussis GV, Elliott P, Estivill X, Evans DM, Feenstra B, Flexeder C, Frayling T, Freathy RM, Gaillard R, Geller F, Gillman M, Grant SF, Groen-Blokhuis M, Goh LK, Guxens M, Hakonarson H, Hattersley AT, Haworth CM, Hadley D, Hebebrand J, Heinrich J, Hinney A, Hirschhorn JN, Hocher B, Holloway JW, Holst C, Hottenga JJ, Horikoshi M, Huikari V, Hypponen E, Iñiguez C, Jaddoe VW, Jarvelin MR, Kaakinen M, Kilpeläinen TO, Kirin M, Kowgier M, Lakka HM, Lakka TA, Lange LA, Lawlor DA, Lehtimäki T, Lewin A, Lindgren C, Lindi V, Maggi R, Marsh J, McCarthy MI, Melbye M, Middeldorp C, Millwood I, Mohlke KL, Mook-Kanamori DO, Murray JC, Nivard M, Nohr EA, Ntalla I, Oken E, Ong KK, O'Reilly PF, Palmer LJ, Panoutsopoulou K, Pararajasingham J, Pearson ER, Pennell CE, Power C, Price TS, Prokopenko I, Raitakari OT, Rodriguez A, Salem RM, Saw SM, Scherag A, Sebert S, Siitonen N, Simell O, Sørensen TI, Sovio U, Pourcain BS, Strachan DP, Sunyer J, Taal HR, Teo YY, Thiering E, Tiesler C, Timpson NJ, Uitterlinden AG, Valcárcel B, Warrington NM, White S, Widén E, Willemsen G, Wilson JF, Yaghootkar H, Zeggini E, Elks CE, Perry JR, Sulem P, Chasman DI, Franceschini N, He C, Lunetta KL, Visser JA, Byrne EM, Cousminer DL, Gudbjartsson DF, Esko T, Feenstra B, Hottenga JJ, Koller DL, Kutalik Z, Lin P, Mangino M, Marongiu M, McArdle PF, Smith AV, Stolk L, van Wingerden SH, Zhao JH, Albrecht E, Corre T, Ingelsson E, Hayward C, Magnusson PK, Smith EN, Ulivi S, Warrington M, Zgaga L, Alavere H, Amin N, Aspelund T, Bandinelli S, Barroso I, Berenson GS, Bergmann S, Blackburn H, Boerwinkle E, Buring JE, Busonero F, Campbell H, Chanock SJ, Chen W, Cornelis MC, Couper D, Coviello AD, d'Adamo P, de Faire U, de Geus EJ, Deloukas P, Döring A, Davey Smith G, Easton DF, Eiriksdottir G, Emilsson V, Eriksson J, Ferrucci L, Folsom AR, Foroud T, Garcia M, Gasparini P, Geller F, Gieger C, Gudnason V, Hall P, Hankinson SE, Ferreli L, Heath AC, Hernandez DG, Hofman A, Hu FB, Illig T, Järvelin MR, Johnson AD, Karasik D, Khaw KT, Kiel DP, Kilpeläinen TO, Kolcic I, Kraft P, Launer LJ, Laven JS, Li S, Liu J, Levy D, Martin NG, McArdle WL, Melbye M, Mooser V, Murray JC, Murray SS, Nalls MA, Navarro P, Nelis M, Ness AR, Northstone K, Oostra BA, Peacock M, Palmer LJ, Palotie A, Paré G, Parker AN, Pedersen NL, Peltonen L, Pennell CE, Pharoah P, Polasek O, Plump AS, Pouta A, Porcu E, Rafnar T, Rice JP, Ring SM, Rivadeneira F, Rudan I, Sala C, Salomaa V, Sanna S, Schlessinger D, Schork NJ, Scuteri A, Segrè AV, Shuldiner AR, Soranzo N, Sovio U, Srinivasan SR, Strachan DP, Tammesoo ML, Tikkanen E, Toniolo D, Tsui K, Tryggvadottir L, Tyrer J, Uda M, van Dam RM, van Meurs JB, Vollenweider P, Waeber G, Wareham NJ, Waterworth DM, Weedon MN, Wichmann HE, Willemsen G, Wilson JF, Wright AF, Young L, Zhai G, Zhuang WV, Bierut LJ, Boyd HA, Crisponi L, Demerath EW, van Duijn CM, Econs MJ, Harris TB, Hunter DJ, Loos RJ, Metspalu A, Montgomery GW, Ridker PM, Spector TD, Streeten EA, Stefansson K, Thorsteinsdottir U, Uitterlinden AG, Widen E, Murabito JM, Ong KK, Murray A.
THE PRICE FOUNDATION COLLABORATIVE GROUP Harry Brandt, Steve Crawford, Scott Crow, Manfred M Fichter, Katherine A Halmi, Craig Johnson, Allan S Kaplan, Maria La Via, James Mitchell, Michael Strober, Alessandro Rotondo, Janet Treasure, D Blake Woodside, Cynthia M Bulik, Pamela Keel, Kelly L Klump, Lisa Lilenfeld, Laura M Thornton, Kathy Plotnicov, Andrew W Bergen, Wade Berrettini, Walter Kaye and Pierre Magistretti.
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Hinney, A., Kesselmeier, M., Jall, S. et al. Evidence for three genetic loci involved in both anorexia nervosa risk and variation of body mass index. Mol Psychiatry 22, 192–201 (2017). https://doi.org/10.1038/mp.2016.71
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DOI: https://doi.org/10.1038/mp.2016.71
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