Anorexia nervosa (AN) and related eating disorders are complex, multifactorial neuropsychiatric conditions with likely rare and common genetic and environmental determinants. To identify genetic variants associated with AN, we pursued a series of sequencing and genotyping studies focusing on the coding regions and upstream sequence of 152 candidate genes in a total of 1205 AN cases and 1948 controls. We identified individual variant associations in the Estrogen Receptor-ß (ESR2) gene, as well as a set of rare and common variants in the Epoxide Hydrolase 2 (EPHX2) gene, in an initial sequencing study of 261 early-onset severe AN cases and 73 controls (P=0.0004). The association of EPHX2 variants was further delineated in: (1) a pooling-based replication study involving an additional 500 AN patients and 500 controls (replication set P=0.00000016); (2) single-locus studies in a cohort of 386 previously genotyped broadly defined AN cases and 295 female population controls from the Bogalusa Heart Study (BHS) and a cohort of 58 individuals with self-reported eating disturbances and 851 controls (combined smallest single locus P<0.01). As EPHX2 is known to influence cholesterol metabolism, and AN is often associated with elevated cholesterol levels, we also investigated the association of EPHX2 variants and longitudinal body mass index (BMI) and cholesterol in BHS female and male subjects (N=229) and found evidence for a modifying effect of a subset of variants on the relationship between cholesterol and BMI (P<0.01). These findings suggest a novel association of gene variants within EPHX2 to susceptibility to AN and provide a foundation for future study of this important yet poorly understood condition.
Bibliographical noteFunding Information:
This study was made possible by a generous gift from the Price Foundation. AVZ, CSB, RT, VB, AT, AC, PP, TP, NV, RT, GZ, SL, SM and NJS are all supported in part by NIH grant 5 UL1 RR025774 and Scripps Genomic Medicine. NJS and his laboratory are also supported in part by NIH grants; 5 U01 DA024417, 5 R01 HL089655, 5 R01 DA030976, 5 R01 AG035020, 1 R01 MH093500, 2 U19 AI063603, 2 U19 AG023122, 5 P01 AG027734 as well as the Stand Up To Cancer Foundation. M Strober receives support from the Resnick Chair in Eating Disorders. B Shih is in part supported by 5K01DK087813-02, and CSB is in part supported by NIH grant 1R21HG005747-01. The Price Foundation Collaborative Group has been responsible for the data collection, curation, management and oversight of the DNA samples used in this report. The members of this group have also provided feedback on this and other reports making use of the samples.
- anorexia nervosa