Genome-Wide Association Study Reveals First Locus for Anorexia Nervosa and Metabolic Correlations

Abstract

Anorexia nervosa (AN) is a serious eating disorder characterized by restriction of energy intake relative to requirements, resulting in abnormally low body weight. It has a lifetime prevalence of approximately 1%, disproportionately affects females 1,2 , and has no well replicated evidence of effective pharmacological or psychological treatments despite high morbidity and mortality 2 .Twin studies support a genetic basis for the observed aggregation of AN in families 3 , with heritability estimates of 48%-74% 4 . Although initial genome-wide association studies (GWASs) were underpowered 5,6 , evidence suggested that signals for AN would be detected with increased power 5 . We present a GWAS of 3,495 AN cases and 10,982 controls with one genome-wide significant locus (index variant rs4622308, p=4.3x10 -9 ) in a region (chr12: 56,372,482,185) which includes six genes. The SNP-chip heritability (h "#$ % ) of AN from these data is 0.20 (SE=0.02), suggesting that a substantial fraction of the twin-based heritability stems from common genetic variation. Using these GWAS results, we also find significant positive genetic correlations with schizophrenia, neuroticism, educational attainment, and HDL cholesterol, and significant negative genetic correlations with body mass, insulin, glucose, and lipid phenotypes.Our results support the reconceptualization of AN as a disorder with both psychiatric and metabolic components.Following uniform quality control and imputation using the 1000 Genomes Project (phase 3) 7 in 12 anorexia nervosa (AN) case-control cohorts, we performed association analysis using an additive model on the dosage data for each cohort and an inverse-variance weighted metaanalysis across cohorts (see Supplementary Text for methods, quality control details and see Supplementary Table S1 for individual study details). Results were obtained for 10,641,224SNPs and insertion-deletion variants with minor allele frequency > 1% and imputation quality scores > 0.6 (see Supplementary Figure S1 for quantile-quantile plot). GWAS statistic inflation ( ) was 1.045, and the sample size adjusted '((( was 1.008, suggesting minimal inflation due to population stratification or other systematic biases.One locus achieved genome-wide significance for AN (Figure 1). Information for the top ten loci is given in Supplementary Table S2. The chromosome 12 (12q13.2) locus reported here is multigenic, overlaps six genes (IKZF4, RPS26, ERBB3, PA2G4, RPL41, and ZC3H10), and is located near six additional genes (ESYT1, SUOX, RAB5B, CDK2, PMEL, and DGKA).Supplementary Figure S2 provides a forest plot and information about effects across cohorts for the top SNP (rs4622308, P=4.3x10 -9 , OR (C allele) =1.2, SE=0.03, MAF cases =0.48, MAF controls =0.44), which were relatively consistent across cohorts. Results of conditional analyses are consistent with the existence of one signal at this locus (see Supplementary Figure S3). Several other immune-related phenotypes: vitiligo, alopecia areata, and asthma (see Supplementary Figure S4) have a...

The Science Behind the Academy for Eating Disorders' Nine Truths About Eating Disorders

“…Although higher parental education has been associated with increased risk of being diagnosed with an eating disorder in registry studies (Ahrén et al, ; Goodman, Heshmati, & Koupil, ), evidence suggests that this association may be genetically rather than socially mediated (Duncan et al, ). No consistent association has been observed between socioeconomic status and risk of eating disorders (Mitchison & Hay, ).…”

“…Genome‐wide association studies (GWASs), which scan the entire genome in a hypothesis‐free manner, and related approaches such as exome sequencing and whole‐genome sequencing have rapidly accelerated the field. The Eating Disorders Working Group of the Psychiatric Genomics Consortium recently identified the first genome‐wide significant locus for AN (Duncan et al, ) in an area that harbours genes previously implicated in type 1 diabetes and other autoimmune disorders. We expect this will mark an inflection point in genomic discovery if AN follows the same progression of findings as other psychiatric disorders such as schizophrenia, where increased sample size has led to fruitful genomic discovery (Schizophrenia Working Group of the Psychiatric Genomics Consortium, ).…”

Identifying tissues implicated in Anorexia Nervosa using Transcriptomic Imputation

“…We identified a number of genomic regions with multiple associations, as well as genes with significant associations across multiple tissues. In particular, we identified a very large number of gene-tissue associations (35 significant gene-tissue associations), in the same chromosome locus identified in a recent GWAS by the PGC-ED group 20 .…”

5‐HT2AR and BDNF gene variants in eating disorders susceptibility

“…For example, two collaborative studies, using a large European population (Ribasés et al, , ), and a meta‐analysis of case–control studies (Gratacòs et al, ) confirm the involvement of BDNF in ED subtypes, particularly restricting AN. Nevertheless, this association was not found by Boraska et al () in a genome‐wide association study as well as in more recent studies (Duncan et al, ; Watson et al, ).…”