2/3 Eating Disorders Genetics Initiative 2 - 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 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) to identify biologically, clinically, and therapeutically meaningful and actionable insights. Inclusion of foreign sites is essential to achieve the large sample sizes required for genetic discovery; our discoveries will improve understanding and treatment of eating disorders 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 (BN), binge-eating disorder (BED), avoidant/restrictive food intake disorder (ARFID), and controls,over-sampling those with severe and enduring AN whose DNA may be enriched for causative alleles. Aim 2: We will apply statistical genetic analyses to explicate ED heterogeneity and biology by: conducting GWAS of diagnoses, trans-diagnostic behaviors, and continuous phenotypes including polygenic risk score (PRS), and rare variant CNV analyses; identifying clinically meaningfully patient subsets; and evaluating our proposal that AN is a metabo-psychiatric disorder using LDSC, PRSet, pheWAS, and Mendelian randomization to clarify causation direction. Aim 3: We will assess 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 by genotypically characterizing those with severe ED phenotypes. We will identify genetic or molecular patterns across cases and controls and phenotypically characterize identified molecular subtypes. Aim 4: To determine where 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 implicated by the genomics of each ED; expand to relevant non-brain cell types; and use dynamic GREx to model gene expression in ED-relevant contexts (e.g., sex, BMI) enabling precise, personalized modelling of gene expression. Aim 5: EDGI2 will culminate in a Translational Summit 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.
