Rare CRHR2 and GRM8 variants identified as candidate factors associated with eating disorders in Japanese patients by whole exome sequencing

Abstract

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 helix region, while the SNV of GRM8 was found to contribute to hydrogen bonds for an α-helix structure. CRHR2 plays important roles in the serotoninergic system of dorsal raphe nuclei, which is involved with feeding and stress-coping behavior, whereas GRM8 modulates glutamatergic neurotransmission. Moreover, GRM8 modulates glutamatergic neurotransmission, and is also considered to have effects on dopaminergic and adrenergic neurotransmission. Thus, identification of rare and deleterious variants in this study is expected to increase understanding and treatment of affected individuals. Further investigation regarding the biological function of these variants may provide an opportunity to elucidate the pathogenesis of EDs.

Keywords: Affected sib-pair; CRHR2; Eating disorder; GRM8; Whole exome sequencing.

Fig. 1

Sib-pair families affected by EDs were examined using whole exome sequencing. Individuals labeled with an ID number were sequenced. The disease phenotype of affected sib-pairs in the P15 family was transferred from ANR to BN. The rare variants GRM8 and CRHR2 were observed in the P4 and P15 families, respectively. Abbreviations: ANR, anorexia nervosa restricting type BN, bulimia nervosa.

Fig. 2

Scheme for screening variants with whole exome sequencing.

Fig. 3

Multiple amino acid sequence alignments of TM4 helix of human class B GPCRs and CRHR2 in various species. Upper alignment indicates TM4 of a selected set of human class B GPCRs included with the GWG x P motif involved in cholesterol binding. Lower alignment indicates evolutionarily conserved amino acids. The level of blue shading is shown according to sequence conservation. Black square indicates amino acid position corresponding to human G231.