The role of leptin, melanocortin, and neurotrophin system genes on body weight in anorexia nervosa and bulimia nervosa

Zeynep Yilmaz; Allan S Kaplan; Arun K Tiwari; Robert D Levitan; Sara Piran; Andrew W Bergen; Walter H Kaye; Hakon Hakonarson; Kai Wang; Wade H Berrettini; Harry A Brandt; Cynthia M Bulik; Steven Crawford; Scott Crow; Manfred M Fichter; Katherine A Halmi; Craig L Johnson; Pamela K Keel; Kelly L Klump; Pierre Magistretti; James E Mitchell; Michael Strober; Laura M Thornton; Janet Treasure; D Blake Woodside; Joanne Knight; James L Kennedy

doi:10.1016/j.jpsychires.2014.04.005

The role of leptin, melanocortin, and neurotrophin system genes on body weight in anorexia nervosa and bulimia nervosa

J Psychiatr Res. 2014 Aug:55:77-86. doi: 10.1016/j.jpsychires.2014.04.005. Epub 2014 Apr 16.

Authors

Zeynep Yilmaz¹, Allan S Kaplan², Arun K Tiwari³, Robert D Levitan⁴, Sara Piran⁵, Andrew W Bergen⁶, Walter H Kaye⁷, Hakon Hakonarson⁸, Kai Wang⁹, Wade H Berrettini¹⁰, Harry A Brandt¹¹, Cynthia M Bulik¹², Steven Crawford¹¹, Scott Crow¹³, Manfred M Fichter¹⁴, Katherine A Halmi¹⁵, Craig L Johnson¹⁶, Pamela K Keel¹⁷, Kelly L Klump¹⁸, Pierre Magistretti¹⁹, James E Mitchell²⁰, Michael Strober²¹, Laura M Thornton²², Janet Treasure²³, D Blake Woodside²⁴, Joanne Knight²⁵, James L Kennedy²⁶

Affiliations

¹ Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Clinical Research Department, Centre for Addiction and Mental Health, Toronto, Canada.
² Clinical Research Department, Centre for Addiction and Mental Health, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada; Department of Psychiatry, University of Toronto, Toronto, Canada.
³ Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, Canada.
⁴ Institute of Medical Science, University of Toronto, Toronto, Canada; Department of Psychiatry, University of Toronto, Toronto, Canada; Mood and Anxiety Program, Centre for Addiction and Mental Health, Toronto, Canada.
⁵ Faculty of Medicine, University of Ottawa, Ottawa, Canada.
⁶ Center for Health Sciences, SRI International, Menlo Park, CA, USA.
⁷ Department of Psychiatry, University of California, San Diego, CA, USA.
⁸ Joseph Stokes Jr. Research Institute, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁹ Department of Psychiatry, University of Southern California, Los Angeles, CA, USA.
¹⁰ Department of Psychiatry, Center of Neurobiology and Behavior, University of Pennsylvania, Philadelphia, PA, USA.
¹¹ Department of Psychiatry, Sheppard Pratt Health System, Towson, MD, USA.
¹² Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹³ Department of Psychiatry, University of Minnesota, Minneapolis, MN, USA.
¹⁴ Department of Psychiatry, University of Munich (LMU), Munich, Germany; Roseneck Hospital for Behavioral Medicine, Prien, Germany.
¹⁵ Department of Psychiatry, Weill Cornell Medical College, New York, NY, USA.
¹⁶ Eating Recovery Center, Denver, CO, USA.
¹⁷ Department of Psychology, Florida State University, Tallahassee, FL, USA.
¹⁸ Department of Psychology, Michigan State University, East Lansing, MI, USA.
¹⁹ Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
²⁰ Department of Clinical Neuroscience, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA; Neuropsychiatric Research Institute, Fargo, ND, USA.
²¹ Department of Psychiatry, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
²² Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
²³ Department of Academic Psychiatry, King's College London, Institute of Psychiatry, London, United Kingdom.
²⁴ Department of Psychiatry, University of Toronto, Toronto, Canada; Eating Disorders Program, Toronto General Hospital, Toronto, Canada.
²⁵ Institute of Medical Science, University of Toronto, Toronto, Canada; Department of Psychiatry, University of Toronto, Toronto, Canada; Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, Canada.
²⁶ Institute of Medical Science, University of Toronto, Toronto, Canada; Department of Psychiatry, University of Toronto, Toronto, Canada; Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, Canada. Electronic address: [email protected].

Abstract

Objective: Although low weight is a key factor contributing to the high mortality in anorexia nervosa (AN), it is unclear how AN patients sustain low weight compared with bulimia nervosa (BN) patients with similar psychopathology. Studies of genes involved in appetite and weight regulation in eating disorders have yielded variable findings, in part due to small sample size and clinical heterogeneity. This study: (1) assessed the role of leptin, melanocortin, and neurotrophin genetic variants in conferring risk for AN and BN; and (2) explored the involvement of these genes in body mass index (BMI) variations within AN and BN.

Method: Our sample consisted of 745 individuals with AN without a history of BN, 245 individuals with BN without a history of AN, and 321 controls. We genotyped 20 markers with known or putative function among genes selected from leptin, melanocortin, and neurotrophin systems.

Results: There were no significant differences in allele frequencies among individuals with AN, BN, and controls. AGRP rs13338499 polymorphism was associated with lowest illness-related BMI in those with AN (p = 0.0013), and NTRK2 rs1042571 was associated with highest BMI in those with BN (p = 0.0018).

Discussion: To our knowledge, this is the first study to address the issue of clinical heterogeneity in eating disorder genetic research and to explore the role of known or putatively functional markers in genes regulating appetite and weight in individuals with AN and BN. If replicated, our results may serve as an important first step toward gaining a better understanding of weight regulation in eating disorders.

Keywords: Anorexia nervosa; Body weight; Bulimia nervosa; Candidate gene association; Melanocortins; Neurotrophins.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Agouti-Related Protein / genetics
Anorexia Nervosa / genetics*
Anorexia Nervosa / physiopathology
Body Mass Index
Body Weight / genetics*
Bulimia Nervosa / genetics*
Bulimia Nervosa / physiopathology
Case-Control Studies
Female
Genotyping Techniques
Humans
Leptin / genetics*
Melanocortins / genetics*
Membrane Glycoproteins
Middle Aged
Nerve Growth Factors / genetics*
Polymorphism, Single Nucleotide
Protein Kinases / genetics
Protein-Tyrosine Kinases
Receptor, trkB

Substances

AGRP protein, human
Agouti-Related Protein
Leptin
Melanocortins
Membrane Glycoproteins
Nerve Growth Factors
Protein Kinases
Protein-Tyrosine Kinases
Receptor, trkB
tropomyosin-related kinase-B, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding