3/3 Eating Disorders Genetics Initiative 2 (EDGI2) - 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 predecessors, EDGI1 (R01 MH120170) and ARFID-GEN (R56 MH129437), were highly successful. We unite the three global EDGI1 sites to advance genomic discovery across major eating disorders (EDs) and identify biologically, clinically, and therapeutically actionable insights. Inclusion of foreign sites is essential to achieve the large sample sizes required for genetic discovery; these discoveries will improve understanding and treatment of EDs in the U.S. Aim 1: EDGI2 will increase sample size, geographic origins, and ED phenotypes. Using our harmonized online assessment battery, we will phenotype and bio-sample 20,000 new participants with anorexia nervosa (AN), bulimia nervosa, binge-eating disorder, avoidant/restrictive food intake disorder, and controls, over-sampling severe and enduring AN, whose DNA may be enriched for causative alleles. Aim 2: We will explicate ED heterogeneity and biology by conducting standard genomic analyses (GWAS of diagnoses, trans-diagnostic behaviors, and continuous traits, PRS, and rare variant CNV); identifying clinically meaningful subgroups; and evaluating that AN is a metabo-psychiatric disorder using LDSC, PRSet, pheWAS, and Mendelian randomization to clarify causal direction. Aim 3: We will assess genetic and environmental risk and resilience factors to inform prediction by phenotypically characterizing cases and controls with high and low PRS for EDs and then by genotypically characterizing those with severe phenotypes. We will identify genetic or molecular patterns across cases and controls and phenotypically characterize identified 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.
