Genomic Analyses Identify Rare Variants in Genes Associated with Age at Menarche in Patients Affected with Anorexia Nervosa and Support a Role for Puberty Timing in Anorexia Nervosa Risk

Author(s): Nicolas Lebrun, Philibert Duriez, Julia Clarke, Philip Gorwood, Nicolas Ramoz, Thierry Bienvenu

Puberty is a critical risk period for eating disorders, especially in girls. Previous reports showed that the association between puberty and eating disorders is mainly due to genetic factors, but the nature of these factors is unclear. To identify these genetic factors, we carried out exome analysis in 10 girls with anorexia nervosa compared to 10 unaffected women controls and identified low-frequency variants in genes among a list of 185 puberty-associated genes. After filtering data, 9 controls and 9 affected girls had at least one potential pathogenic rare (PPR) variant. In controls, 35 PPR variants were identified located (in 31 genes) whereas 52 PPR variants (in 38 genes) were identified in patients with AN. Among the genes identified only in the AN patients, we found a significant enrichment as compared to the general population and the control sample, in variants previously identified as associated with age at menarche (TNRC6A, LAMB2 and FAAH2). Two AN patients presented at least one rare missense variant in these genes. Moreover, nine patients with AN carried out missense/frameshift variants in puberty-associated genes previously identified by GWAS studies. Our results suggest that rare variants in genes involved in the timing of puberty such as TNRC6A, LAMB2 and FAAH2 may predispose to anorexia nervosa susceptibility during puberty.