Rare CRHR2 and GRM8 variants identified as candidate factors associated with eating disorders in Japanese patients.

Eating disorders (EDs) are a type of psychiatric disorder characterized by pathological eating and related behavior and considered to be highly heritable. The purpose of this study was to explore rare variants expected to display biological functions associated with the etiology of EDs. We performed whole exome sequencing (WES) of affected sib-pairs corresponding to disease subtype through their lifetime and their parents. From those results, rare single nucleotide variants (SNVs) concordant with sib-pairs were extracted and estimated to be most deleterious in the examined families. Two non-synonymous SNVs located on corticotropin releasing hormone receptor 2 (CRHR2) and glutamate metabotropic receptor 8 (GRM8) were identified as candidate disease susceptibility factors. The SNV of CRHR2 was included within the cholesterol binding motif of the transmembrane helices region, while the SNV of GRM8 was found to contribute to hydrogen bonds for an -helix structure. CRHR2 plays important roles in the serotoninergic system of dorsal raphe nuclei, which is involved with feeding and stress-coping behavior. Moreover, GRM8 modulates glutamatergic neurotransmission, and is also considered to have effects on dopaminergic and adrenergic neurotransmission. Further investigation regarding the biological function of these variants may provide an opportunity for elucidate the pathogenesis of EDs.