A genome-wide association study of anorexia nervosa suggests a risk locus implicated in dysregulated leptin signaling

Abstract

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 × 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.

Anorexia Nervosa

“…Research on candidate genes examined the serotonergic system (5-HT system), dopaminergic system, and opioidergic system that affect appetite, reward mechanism, mood, and weight; nevertheless, statistically significant results have not been presented so far [51]. Genome wide studies showed a relation between chromosomes 1, 11, and 12 and genes related to leptin regulation, lipid and glucose metabolism, serotonin receptor activities, and the immune system [52][53][54][55]. This genetic presentation is also consistent with the clinical presentation of anorexia.…”

An Evolutionary Genetic Perspective of Eating Disorders

“…The inactivation of EBF1 in mice leads to a decrease in circulating leptin levels, in line with the observations of very low leptin levels made in human AN patients. In addition, another SNP (rs4704963) in EBF1 showed genome-wide significant interaction with psychosocial stress on obesity traits [83]. In a sample of 3,495 AN cases and 10,982 controls, rs4622308 near the v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3 (ERBB3) gene was significantly associated with AN [84].…”

“…Only 2 studies to date have identified SNPs significantly associated with AN [83,84]. To gain the statistical power necessary for further genome-wide significant results, research efforts should focus on the recruitment of large case-control cohorts.…”

The association of serum leptin levels with food addiction is moderated by weight status in adolescent psychiatric inpatients

“…After adjustment for BMI four loci in/near LEP, SLC32A1, GCKR, and CCNL1 remained robustly associated with leptin levels (Kilpeläinen et al, ). One study found suggestive evidence for a variant‐mediated (rs929626 in EBF1 : Early B‐Cell Factor 1 gene) disordered leptin signalling in patients with anorexia nervosa (AN; Li et al, ).…”

“…. One study found suggestive evidence for a variant-mediated (rs929626 in EBF1: Early B-Cell Factor 1 gene) disordered leptin signalling in patients with anorexia nervosa (AN; Li et al, 2017).…”