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

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.

Rapid Emergence of Appetite and Hunger Resulting in Weight Gain and Improvement of Eating Disorder Symptomatology during and after Short-Term Off-Label Metreleptin Treatment of a Patient with Anorexia Nervosa

“…Both a higher mean percent body fat and an increased synthesis of leptin per unit of fat mass explain the higher circulating leptin levels in females [ 36 ]. A reduced leptin secretion may predispose to AN [ 37 ]. AN typically manifests during the age period, in which leptin secretion changes substantially in females, potentially entailing a vulnerable period for derailment induced via weight loss.…”

Association of cardiovascular risk factors and lifestyle behaviors with aortic aneurysm: A Mendelian randomization study

“…We also calculated the F statistics for each SNP and used only SNP with F statistics larger than 10 to avoid weak instrument bias ( Burgess and Thompson, 2011 ). Then, for any unavailable SNPs in GWAS for aortic aneurysms, we used SNPs with LD of at least r 2 > 0.80 as an alternative ( Peters et al, 2021 ). At last, we included 210/204 SNPs (UK Biobank/FinnGen) for hypertension ( Elsworth et al, 2019 ), 477/467 for BMI ( Yengo et al, 2018 ), 202/199 for WHR ( Pulit et al, 2019 ), 202/198 for WHRadjBMI ( Pulit et al, 2019 ), 115/114 for type 2 diabetes ( Xue et al, 2018 ), 36/36 for type 1 diabetes ( Onengut-Gumuscu et al, 2015 ), 194/193 for age of smoking initiation ( Liu et al, 2019 ), 118/116 for tobacco use (initiation, cessation, and heaviness) ( Wootton et al, 2020 ), 68/68 for alcohol consumption ( Liu et al, 2019 ), 4/4 for coffee consumption ( Cornelis et al, 2015 ), 19/19 for physical activity ( Klimentidis et al, 2018 ), and 12/12 for sleep duration ( Doherty et al, 2018 ) ( Table 1 ; Supplementary Table S1 ).…”

Restlessness and an Increased Urge to Move (Drive for Activity) in Anorexia Nervosa May Strengthen Personal Motivation to Maintain Caloric Restriction and May Augment Body Awareness and Proprioception: A Lesson From Leptin Administration in Anorexia Nervosa

“…Transport of leptin to the brain is reduced by fasting ( Kastin et al, 2000 ). In a genome-wide meta-analysis, Kilpeläinen (2016) uncovered several loci associated with circulating leptin levels and Peters et al (2021) recently reported a correlation between a genetic predisposition to low leptin levels and risk for AN in females.…”