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

Akira Oka; Shinji Hadano; Mahoko Takahashi Ueda; So Nakagawa; Gen Komaki; Tetsuya Ando

doi:10.1016/j.heliyon.2024.e28643

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

Heliyon. 2024 Mar 26;10(8):e28643. doi: 10.1016/j.heliyon.2024.e28643. eCollection 2024 Apr 30.

Authors

Akira Oka^{1

2}, Shinji Hadano^{2

3

4}, Mahoko Takahashi Ueda⁵, So Nakagawa^{1

2

4}, Gen Komaki⁶, Tetsuya Ando^{7

8}

Affiliations

¹ Department of Molecular Life Sciences, Division of Basic Medical Science and Molecular Medicine, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan.
² The Institute of Medical Sciences, Tokai University, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan.
³ Department of Physiology, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan.
⁴ Micro/Nano Technology Center, Tokai University, Hiratsuka, Kanagawa, 259-1292, Japan.
⁵ Department of Genomic Function and Diversity, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo, Tokyo, 113-8510, Japan.
⁶ Faculty of Medical Science, Fukuoka International University of Health and Welfare, Momochihama, Sawara-ku, Fukuoka, 814-0001, Japan.
⁷ Department of Psychosomatic Medicine, Faculty of Medicine, School of Medicine, International University of Health and Welfare, 4-3 Kozunomori, Narita, Chiba, 286-8686, Japan.
⁸ Department of Behavioral Medicine, National Institute of Mental Health, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi, Kodaira, Tokyo, 187-8553, Japan.

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.