Suggestive Evidence for Causal Effect of Leptin Levels on Risk for Anorexia Nervosa: Results of a Mendelian Randomization Study

Triinu Peters; Jochen Antel; Roaa Naaresh; Björn-Hergen Laabs; Manuel Föcker; Nicola Albers; Judith Bühlmeier; Anke Hinney; Lars Libuda; Johannes Hebebrand

doi:10.3389/fgene.2021.733606

Suggestive Evidence for Causal Effect of Leptin Levels on Risk for Anorexia Nervosa: Results of a Mendelian Randomization Study

Front Genet. 2021 Sep 14:12:733606. doi: 10.3389/fgene.2021.733606. eCollection 2021.

Authors

Affiliations

¹ Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
² Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Universitätsklinikum Schleswig-Holstein, Lübeck, Germany.
³ Department of Child and Adolescent Psychiatry, University of Münster, Münster, Germany.
⁴ Institute of Nutrition, Consumption and Health, Faculty of Natural Sciences, Paderborn University, Paderborn, Germany.
⁵ Evangelisches Krankenhaus Düsseldorf, Children's Hospital, Düsseldorf, Germany.

Abstract

Genetic correlations suggest a coexisting genetic predisposition to both low leptin levels and risk for anorexia nervosa (AN). To investigate the causality and direction of these associations, we performed bidirectional two-sample Mendelian randomization (MR) analyses using data of the most recent genome-wide association study (GWAS) for AN and both a GWAS and an exome-wide-association-study (EWAS) for leptin levels. Most MR methods with genetic instruments from GWAS showed a causal effect of lower leptin levels on higher risk of AN (e.g. IVW b = -0.923, p = 1.5 × 10^-4). Because most patients with AN are female, we additionally performed analyses using leptin GWAS data of females only. Again, there was a significant effect of leptin levels on the risk of AN (e.g. IVW b = -0.826, p = 1.1 × 10^-04). MR with genetic instruments from EWAS showed no overall effect of leptin levels on the risk for AN. For the opposite direction, MR revealed no causal effect of AN on leptin levels. If our results are confirmed in extended GWAS data sets, a low endogenous leptin synthesis represents a risk factor for developing AN.

Keywords: anorexia nervosa; body mass index; hypoleptinemia; leptin levels; mendelian randomization (MR).