3/3 Eating Disorders Genetics Initiative 2 (EDGI2)

PROJECT SUMMARY We propose the Eating Disorders Genetics Initiative 2 (EDGI2), a new collaborative R01 in response to PAR- 23-050 Clinical Studies of Mental Illness. Its single-site predecessors, EDGI1 (R01 MH120170) and ARFID-GEN (R56 MH129437) have been resoundingly successful. We now unite the four original EDGI1 sites with

exceptionally productive global new sites to advance genomic discovery across all major eating disorders (EDs) to identify biologically, clinically, culturally, and therapeutically meaningful and actionable insights. Aim 1: EDGI2 extends our core business by increasing sample size, diversity, and ED phenotypes. Using our comprehensive

harmonized online assessment battery, we will phenotype and bio-sample 20,000 new participants with anorexia nervosa (AN), bulimia nervosa (BN), binge-eating disorder (BED), avoidant/restrictive food intake disorder (ARFID), and controls. EDGI2 emphasizes co-production—with representatives from minoritized and

marginalized communities, we will ascertain 30% of samples from underrepresented groups. We will also over- sample individuals with severe and enduring AN (SE-AN), whose DNA may be enriched for causative alleles. Aim 2: We will apply statistical genetic analyses to explicate heterogeneity and biology of EDs by: conducting

standard GWAS analyses on diagnoses, trans-diagnostic behaviors, and continuous phenotypes including polygenic risk score (PRS), and rare variant CNV analyses; identifying clinically meaningfully patient subsets; and intensively evaluating our proposal that AN is a metabo-psychiatric disorders using LDSC, PRSet, pheWAS,

and Mendelian randomization to clarify direction of causation. Aim 3: We will evaluate the relative roles of genetic and environmental risk and resilience factors to inform risk prediction by phenotypically characterizing cases and controls with high and low PRS for EDs and then by genotypically characterizing those with severe ED

phenotypes. We will characterize distinct genetic or molecular groupings/patterns across cases and controls and phenotypically characterize identified molecular subtypes. Aim 4: To determine where in the body EDs “live”, we will identify brain cell types and anatomical regions implicated by genomic studies of EDs; predict genetically

regulated gene expression (GREx) in brain, gut, adipose, and other ED-relevant tissues; use snRNAseq atlases to sharpen preliminary GTEx and TWAS analyses to identify brain cell types strongly implicated by the genomics of each ED; expand to relevant non-brain cell types (e.g., adipose, muscle, liver, salivary); and use dynamic

GREx to model gene expression in ED-relevant contexts (e.g., sex, BMI, stress) enabling precise and personalized modelling of gene expression. Aim 5: EDGI2 will culminate in a Translational Summit uniting forward-thinking stakeholders from multiple sectors to develop a translational roadmap for evidence-based ED

prevention and treatment. EDGI2 will yield critical knowledge about genetic and environmental risk for EDs, reveal mechanisms that potentiate or protect against genetic risk, and transition ED genetics from discovery to clinical translation.