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

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

doi:10.3389/fgene.2021.733606

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.

Highlights

Leptin plays an essential role in the physiology and pathophysiology of energy homeostasis, endocrinology and metabolism (Berthoud, 2011; Mantzoros et al, 2011; Peelman et al, 2014)
In the analysis with leptin level as exposure (Kilpeläinen et al, 2016) and risk for anorexia nervosa (AN) as outcome including five single nucleotide polymorphisms (SNP) (Table 1), the results were inconsistent depending on the method of analysis (Table 2)
The h2SNP calculated with the LDSC tool for genome-wide association study (GWAS) on leptin levels was 0.097

Summary

Introduction

Leptin plays an essential role in the physiology and pathophysiology of energy homeostasis, endocrinology and metabolism (Berthoud, 2011; Mantzoros et al, 2011; Peelman et al, 2014). Via changing the sensitivity of brain reward circuits to food stimuli (Volkow et al, 2011), leptin has been shown to influence eating behavior and to modulate food intake (Miller, 2011; Hebebrand et al, 2014; Miller et al, 2014; Fernandes et al, 2015; Benbaibeche et al, 2021). Cognition, and behavior, in starvation (Lu, 2007; Morrison, 2009; Higgs et al, 2017; Hebebrand et al, 2019; Zou et al, 2019; Milos et al, 2020; Antel et al, 2021). Leptin binds to leptin receptors which are located in several brain regions and peripheral tissues (Margetic et al, 2002)

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