Genetic association of recovery from eating disorders: the role of GABA receptor SNPs

Abstract

Follow-up studies of eating disorders (EDs) suggest outcomes ranging from recovery to chronic illness or death, but predictors of outcome have not been consistently identified. We tested 5151 single-nucleotide polymorphisms (SNPs) in approximately 350 candidate genes for association with recovery from ED in 1878 women. Initial analyses focused on a strictly defined discovery cohort of women who were over age 25 years, carried a lifetime diagnosis of an ED, and for whom data were available regarding the presence (n=361 ongoing symptoms in the past year, ie, 'ill') or absence (n=115 no symptoms in the past year, ie, 'recovered') of ED symptoms. An intronic SNP (rs17536211) in GABRG1 showed the strongest statistical evidence of association (p=4.63 × 10(-6), false discovery rate (FDR)=0.021, odds ratio (OR)=0.46). We replicated these findings in a more liberally defined cohort of women age 25 years or younger (n=464 ill, n=107 recovered; p=0.0336, OR=0.68; combined sample p=4.57 × 10(-6), FDR=0.0049, OR=0.55). Enrichment analyses revealed that GABA (γ-aminobutyric acid) SNPs were over-represented among SNPs associated at p<0.05 in both the discovery (Z=3.64, p=0.0003) and combined cohorts (Z=2.07, p=0.0388). In follow-up phenomic association analyses with a third independent cohort (n=154 ED cases, n=677 controls), rs17536211 was associated with trait anxiety (p=0.049), suggesting a possible mechanism through which this variant may influence ED outcome. These findings could provide new insights into the development of more effective interventions for the most treatment-resistant patients.

Figure 1

Q–Q plot for genetic association with eating disorder (ED) outcome in discovery sample.

Figure 2

High-resolution Manhattan plot of the GABRG1 and GABRA regions on chromosome 4. Plot shows p-values for each genotyped single-nucleotide polymorphism (SNP), which are color-coded as a function of R² value in relation to rs17536211. As shown, higher R² values correspond to lower p-values with respect to association with eating disorder (ED) outcome, providing additional support for the validity of the original association with rs17536211. Recombination break points are plotted in blue.

Figure 3

Trait anxiety as a function of diagnosis, recovery status, and rs17536211 genotype. As shown, all study groups with the exception of the ill group show lower trait anxiety among minor allele homozygotes, consistent with the statistically significant association between trait anxiety and rs17536211 genotype. Error bars represent the 95% confidence interval.