Mapping anorexia nervosa genes to clinical phenotypes.

Area of Science:

• Genetics
• Psychiatry
• Bioinformatics

Background:

• Anorexia nervosa (AN) is a complex psychiatric disorder with significant genetic contributions.
• Genome-wide association studies (GWAS) identify genetic variants linked to AN.
• Transcriptomic imputation (TI) translates genetic findings into regulatory mechanisms and functional outcomes.

Purpose of the Study:

• To translate AN GWAS findings into genetically regulated gene expression (AN-GReX) using TI.
• To assess the clinical consequences of AN-GReX in a large biobank population.
• To investigate the impact of body mass index (BMI) and sex on AN-GReX clinical associations.

Main Methods:

• Applied S-PrediXcan to translate AN GWAS findings into AN-GReX.
• Imputed AN-GReX in the Mount Sinai BioMe™ Biobank.
• Conducted phenome-wide association studies (pheWASs) on over 2000 outcomes.
• Performed secondary analyses for BMI and sex moderation.

Main Results:

• Identified 53 genes associated with AN, including a novel association with the major histocompatibility complex.
• AN-GReX showed associations with autoimmune, metabolic, and gastrointestinal diagnoses, cholesterol, medications, substance use, and pain.
• BMI moderated AN-GReX associations with cholesterol and substance use; sex moderated associations with celiac disease.

Conclusions:

• BMI-stratified results offer potential functional mechanisms for AN-related genes.
• This approach links genetic predispositions to diverse clinical phenotypes, advancing AN research.