Abstract
Anorexia nervosa is a complex eating disorder with genetic, metabolic, and psychosocial underpinnings. Using genome-wide methods, recent studies have associated many genes with the disorder. We characterized these genes by projecting them into reference transcriptomic atlases of the prenatal and adult human brain to determine where these genes are expressed in fine detail. We found that genes from an induced stem cell study of anorexia nervosa cases are expressed at higher levels in the lateral parabrachial nucleus. Although weaker, expression enrichment of the adult lateral parabrachial is also found with genes from independent genetic studies. Candidate causal genes from the largest genetic study of anorexia nervosa to date were enriched for expression in the arcuate nucleus of the hypothalamus. We also found an enrichment of anorexia nervosa associated genes in the adult and fetal raphe and ventral tegmental areas. Motivated by enrichment of these feeding circuits, we tested if these genes respond to fasting in mice hypothalami, which highlighted the differential expression of Rps26 and Dalrd3. This work improves our understanding of the neurobiology of anorexia nervosa by suggesting disturbances in subcortical appetitive circuits.
Highlights
Anorexia nervosa is a complex eating disorder with genetic, metabolic, and psychosocial underpinnings
Differential expression of genes in induced neural stem cells would represent the downstream effects of genetic risk[25,26]. While these genomic results are limited in sample size and validations, they have provided the first sets of candidate causal genes for anorexia nervosa to date
We present our results of testing if the anorexia nervosa associated genes are enriched for differential expression in fasted mice as an exploratory analysis
Summary
Anorexia nervosa is a complex eating disorder with genetic, metabolic, and psychosocial underpinnings. A transcriptomic study that compared induced neural stem cells of anorexia nervosa patients and controls identified hundreds of differentially expressed genes[21]. Whole-exome sequencing identified damaging rare variants that are associated with disordered e ating[22] These variants were enriched for neuropeptide signalling genes. Using a larger combined cohort, the most recent genome-wide association study (GWAS) meta-analysis identified eight significant risk loci[24] These loci implicate the nearby genes through genomic proximity, but more evidence is needed to determine if they are causal. Differential expression of genes in induced neural stem cells would represent the downstream effects of genetic risk[25,26] While these genomic results are limited in sample size and validations, they have provided the first sets of candidate causal genes for anorexia nervosa to date
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