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

Abstract

Objective To conduct a genome-wide association study (GWAS) of anorexia nervosa and to calculate genetic correlations with a series of psychiatric, educational, and metabolic phenotypes. Method Following uniform quality control and imputation using the 1000 Genomes Project (phase 3) in 12 case-control cohorts comprising 3,495 anorexia nervosa cases and 10,982 controls, we performed standard association analysis followed by a meta-analysis across cohorts. Linkage disequilibrium score regression (LDSC) was used to calculate genome-wide common variant heritability [ hSNP2, partitioned heritability, and genetic correlations (rg)] between anorexia nervosa and other phenotypes. Results Results were obtained for 10,641,224 single nucleotide polymorphisms (SNPs) and insertion-deletion variants with minor allele frequency > 1% and imputation quality scores > 0.6. The hSNP2 of anorexia nervosa was 0.20 (SE=0.02), suggesting that a substantial fraction of the twin-based heritability arises from common genetic variation. We identified one genome-wide significant locus on chromosome 12 (rs4622308, p=4.3×10−9) 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 (HDL) cholesterol, and significant negative genetic correlations between anorexia nervosa and body mass index, insulin, glucose, and lipid phenotypes. Conclusions Anorexia nervosa is a complex heritable phenotype for which we have found the first genome-wide significant locus. Anorexia nervosa also has large and significant genetic correlations with both psychiatric phenotypes and metabolic traits. Our results encourage a reconceptualization of this frequently lethal disorder as one with both psychiatric and metabolic etiology.

Psychiatric Genomics: An Update and an Agenda

“…Are these genetic correlations putatively causal or due to some other process (confounding or bias)? Differences between disorders will be investigated—for example, body mass has a positive genetic correlation with MDD but a negative genetic correlation with anorexia nervosa (50). …”

Genetics of Anorexia Nervosa

“…Currently, three GWAS of AN have been published [19–21] (Table 2), but additional GWAS are underway [22]. The first two GWAS of AN conducted did not find any genome-wide significant results [19, 20].…”

“…The largest and most rigorous GWAS to date included approximately 4,000 AN cases and 11,000 controls [**21]. One locus on chromosome 12 (12q13.2), which included six genes ( IKZF4, RPS26, ERBB3, PA2G4, RPL41, and ZC3H10 ), reached genome-wide significance ( p < 5×10 −8 ) and had a genome-wide common variant heritability of 20%.…”

An Evolutionary Genetic Perspective of Eating Disorders

“…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]. Further replication studies, larger sam-296 ple sizes, and experiments on expression and function are required to gain a better understanding of the role of these genes in AN.…”

“…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.…”