Significant Locus and Metabolic Genetic Correlations Revealed in Genome-Wide Association Study of Anorexia Nervosa

Abstract

Objective: The authors conducted a genome-wide association study of anorexia nervosa and calculated genetic correlations with a series of psychiatric, educational, and metabolic phenotypes.

Method: Following uniform quality control and imputation procedures using the 1000 Genomes Project (phase 3) in 12 case-control cohorts comprising 3,495 anorexia nervosa cases and 10,982 controls, the authors performed standard association analysis followed by a meta-analysis across cohorts. Linkage disequilibrium score regression was used to calculate genome-wide common variant heritability (single-nucleotide polymorphism [SNP]-based heritability [h²_SNP]), partitioned heritability, and genetic correlations (r_g) between anorexia nervosa and 159 other phenotypes.

Results: Results were obtained for 10,641,224 SNPs and insertion-deletion variants with minor allele frequencies >1% and imputation quality scores >0.6. The h²_SNP of anorexia nervosa was 0.20 (SE=0.02), suggesting that a substantial fraction of the twin-based heritability arises from common genetic variation. The authors identified one genome-wide significant locus on chromosome 12 (rs4622308) in a region harboring a previously reported type 1 diabetes and autoimmune disorder locus. Significant positive genetic correlations were observed between anorexia nervosa and schizophrenia, neuroticism, educational attainment, and high-density lipoprotein cholesterol, and significant negative genetic correlations were observed between anorexia nervosa and body mass index, insulin, glucose, and lipid phenotypes.

Conclusions: Anorexia nervosa is a complex heritable phenotype for which this study has uncovered the first genome-wide significant locus. Anorexia nervosa also has large and significant genetic correlations with both psychiatric phenotypes and metabolic traits. The study results encourage a reconceptualization of this frequently lethal disorder as one with both psychiatric and metabolic etiology.

Keywords: Anorexia Nervosa; Diabetes; Eating Disorders; GWAS; Genetics; Metabolism.

Figure 1. Manhattan and regional plot of the genome-wide significant locus for anorexia nervosa

A. Manhattan plot depicts a genome-wide significant locus on chromosome 12. The threshold for significance (see y-axis) is 7.3, which is –log₁₀(5×10⁻⁸). B. Regional LOCUSZOOM plot of the top locus reveals numerous genes in the region. Results depicted here reflect the full meta-analysis. Per text, see Supplementary Figure 1 for area plot with phenotypic associations. The right axis gives recombination rate, depicted with a light blue line.

Figure 2. Genetic correlations between anorexia nervosa and diverse phenotypes reveal overlap across psychiatric, educational, weight, insulin, lipoprotein, and cholesterol phenotypes

The 24 correlations depicted here (of 159 phenotypes tested) have FDR<0.05. Bars are ± standard error.