Genetic variants identified in novel candidate genes for anorexia nervosa and analysis of molecular pathways for diagnostic applications

Objective: Anorexia nervosa (AN) is a severe psychiatric disorder characterized by an intense fear of gaining weight, a relentless pursuit of thinness, and a distorted body image. Recent research highlights the substantial contribution of genetics to AN's etiology, with genes like BDNF, SLC6A4, and DRD2 implicated. However, a comprehensive genetic test for AN diagnosis is lacking. This study aims to elucidate the biological foundations of AN, examining variants in genes associated with syndromic forms, rare variants in AN patients, and candidate genes from GWAS studies, murine models, or established molecular pathways. Materials and methods: The study involved 135 AN patients from Italy, diagnosed based on DSM-V criteria. A specialized Next-Generation Sequencing panel targeting 163 genes was designed. Sequencing was performed on an Illumina MiSeq System, and variants were analyzed using bioinformatics tools. Data on clinical parameters, exercise habits, and AN types were collected. Results: The AN cohort, predominantly female, exhibited diverse clinical characteristics. Our analysis identified gene variants associated with syndromic forms of AN, such as STRA6, NF1, MAT1A, and ABCC6. Variants were also found in known AN-related genes (CD36, DRD4, GCKR, GHRL, GRIN3B, GPR55, LEPR) and in other 16 candidate genes (A2M, AEBP1, ABHD4, ACBD7, CNTNAP, GFRAL, GRIN2D, LIPE, LMNA, NMU, PDE3B, POMC, RYR1, TNXB, TYK2, VPS13B), highlighting the complexity of AN's genetic landscape. The endocannabinoid and dopamine pathways play crucial roles. Skeletal muscle-related genes and appetite-regulating hormones also revealed potential connections. Adipogenesis-related genes suggest AN's association with subcutaneous adipose tissue deficiency. Conclusions: This study provides comprehensive insights into the genetic underpinnings of AN, emphasizing the importance of multiple pathways. The identified variants contribute.