[en] We conducted a genome-wide association study (GWAS) of anorexia nervosa (AN) using a stringently defined phenotype. Analysis of phenotypic variability led to the identification of a specific genetic risk factor that approached genome-wide significance (rs929626 in EBF1 (Early B-Cell Factor 1); P = 2.04 x 10(-7); OR = 0.7; 95% confidence interval (CI) = 0.61-0.8) with independent replication (P = 0.04), suggesting a variant-mediated dysregulation of leptin signaling may play a role in AN. Multiple SNPs in LD with the variant support the nominal association. This demonstrates that although the clinical and etiologic heterogeneity of AN is universally recognized, further careful sub-typing of cases may provide more precise genomic signals. In this study, through a refinement of the phenotype spectrum of AN, we present a replicable GWAS signal that is nominally associated with AN, highlighting a potentially important candidate locus for further investigation.
Klump, K. L., Bulik, C. M., Kaye, W. H., Treasure, J., Tyson, E. Academy for eating disorders position paper: Eating disorders are serious mental illnesses. Int J Eat Disord 42, 97-103, doi:10.1002/eat.20589 (2009).
Zipfel, S., Giel, K. E., Bulik, C. M., Hay, P., Schmidt, U. Anorexia nervosa: Aetiology, assessment, treatment. Lancet Psychiatry 2, 1099-1111, doi:10.1016/S2215-0366(15)00356-9 (2015).
Hinney, A., Volckmar, A. L. Genetics of eating disorders. Curr Psychiatry Rep 15, 423, doi:10.1007/s11920-013-0423-y (2013).
Bulik, C. M., Slof-Op't Landt, M. C., van Furth, E. F., Sullivan, P. F. The genetics of anorexia nervosa. Annu Rev Nutr 27, 263-275, doi:10.1146/annurev.nutr.27.061406.093713 (2007).
Clarke, T. K., Weiss, A. R., Berrettini, W. H. The genetics of anorexia nervosa. Clin Pharmacol Ther 91, 181-188, doi:10.1038/clpt.2011.253 (2012).
Bulik, C. M., et al. Prevalence, heritability, prospective risk factors for anorexia nervosa. Arch Gen Psychiatry 63, 305-312, doi:10.1001/archpsyc.63.3.305 (2006).
Pinheiro, A. P., Root, T., Bulik, C. M. The Genetics of Anorexia Nervosa: Current Findings and Future Perspectives. Int J Child Adolesc health 2, 153-164 (2009).
Wang, K., et al. A genome-wide association study on common SNPs and rare CNVs in anorexia nervosa. Mol Psychiatry 16, 949-959, doi:10.1038/mp.2010.107 (2011).
Scott-Van Zeeland, A. A., et al. Evidence for the role of EPHX2 gene variants in anorexia nervosa. Mol Psychiatry 19, 724-732, doi:10.1038/mp.2013.91 (2014).
Boraska, V., et al. A genome-wide association study of anorexia nervosa. Mol Psychiatry 19, 1085-1094, doi:10.1038/mp.2013.187 (2014).
Fichter, M., Quadflieg, N. The structured interview for anorexic and bulimic disorders for DSM-IV and ICD-10 (SIAB-EX): Reliability and validity. Eur Psychiatry 16, 38-48, doi:10.1016/S0924-9338(00)00534-4 (2001).
Eddy, K. T., et al. Diagnostic crossover in anorexia nervosa and bulimia nervosa: Implications for DSM-V. Am J Psychiatry 165, 245-250, doi:10.1176/appi.ajp.2007.07060951 (2008).
Bulik, C. M., et al. Understanding the relation between anorexia nervosa and bulimia nervosa in a Swedish national twin sample. Biol Psychiatry 67, 71-77, doi:10.1016/j.biopsych.2009.08.010 (2010).
Consortium, T. E. P. An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57-74, doi:10.1038/nature11247 (2012).
Ward, L. D., Kellis, M. HaploReg: A resource for exploring chromatin states, conservation, regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res 40, D930-934, doi:10.1093/nar/gkr917 (2012).
Teicher, M. H., et al. Functional deficits in basal ganglia of children with attention-deficit/hyperactivity disorder shown with functional magnetic resonance imaging relaxometry. Nat Med 6, 470-473, doi:10.1038/74737 (2000).
Radua, J., Mataix-Cols, D. Voxel-wise meta-analysis of grey matter changes in obsessive-compulsive disorder. Br J Psychiatry 195, 393-402, doi:10.1192/bjp.bp.108.055046 (2009).
Radua, J., van den Heuvel, O. A., Surguladze, S., Mataix-Cols, D. Meta-analytical comparison of voxel-based morphometry studies in obsessive-compulsive disorder vs other anxiety disorders. Arch Gen Psychiatry 67, 701-711, doi:10.1001/archgenpsychiatry.2010.70 (2010).
Lukin, K., Fields, S., Hartley, J., Hagman, J. Early B cell factor: Regulator of B lineage specification and commitment. Semin Immunol 20, 221-227, doi:10.1016/j.smim.2008.07.004 (2008).
Hesslein, D. G., et al. Ebf1-dependent control of the osteoblast and adipocyte lineages. Bone 44, 537-546, doi:10.1016/j. bone.2008.11.021 (2009).
Akerblad, P., Lind, U., Liberg, D., Bamberg, K., Sigvardsson, M. Early B-cell factor (O/E-1) is a promoter of adipogenesis and involved in control of genes important for terminal adipocyte differentiation. Mol Cell Biol 22, 8015-8025, doi:10.1128/MCB.22.22.8015-8025.2002 (2002).
Jimenez, M. A., Akerblad, P., Sigvardsson, M., Rosen, E. D. Critical role for Ebf1 and Ebf2 in the adipogenic transcriptional cascade. Mol Cell Biol 27, 743-757, doi:10.1128/MCB.01557-06 (2007).
Ehret, G. B., et al. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature 478, 103-109, doi:10.1038/nature10405 (2011).
Wain, L. V., et al. Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure. Nat Genet 43, 1005-1011, doi:10.1038/ng.922 (2011).
Singh, A., et al. Gene by stress genome-wide interaction analysis and path analysis identify EBF1 as a cardiovascular and metabolic risk gene. Eur J Hum Genet 23, 854-862, doi:10.1038/ejhg.2014.189 (2015).
Fretz, J. A., et al. Altered metabolism and lipodystrophy in the early B-cell factor 1-deficient mouse. Endocrinology 151, 1611-1621, doi:10.1210/en.2009-0987 (2010).
Bredella, M. A., et al. Increased bone marrow fat in anorexia nervosa. J Clin Endocrinol Metab 94, 2129-2136, doi:10.1210/jc.2008-2532 (2009).
Abella, E., et al. Bone marrow changes in anorexia nervosa are correlated with the amount of weight loss and not with other clinical findings. Am J Clin Pathol 118, 582-588, doi:10.1309/2Y7X-YDXK-006B-XLT2 (2002).
Haluzik, M., Papezova, M., Nedvidkova, J., Kabrt, J. Serum leptin levels in patients with anorexia nervosa before and after partial refeeding, relationships to serum lipids and biochemical nutritional parameters. Physiol Res 48, 197-202 (1999).
Kilic, M., Taskin, E., Ustundag, B., Aygun, A. D. The evaluation of serum leptin level and other hormonal parameters in children with severe malnutrition. Clin Biochem 37, 382-387, doi:10.1016/j.clinbiochem.2003.12.010 (2004).
Purcell, S., et al. PLINK: A tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81, 559-575, doi:10.1086/519795 (2007).