Project Summary We propose to rapidly accelerate our understanding of the biology of eating disorders by conducting the first genomic study of avoidant/restrictive food intake disorder (ARFID): ARFID-GEN. ARFID, first included in the DSM-5 Feeding and Eating Disorders chapter in 2013, is characterized by food avoidance or restriction due to three non-mutually exclusive presentations (1) phobic avoidance, (2) sensory sensitivity, or (3) disinterest/low appetite. Little is known about risk mechanisms and pathophysiology of ARFID, and no genetic studies have been conducted to date. Ongoing is the Eating Disorders Genetic Initiative (EDGI; R01MH120170), aimed to further the genomic discovery of the eating disorders: anorexia nervosa, bulimia nervosa, and binge-eating disorder. Absent from EDGI is the serious, taxing, and potentially life-threatening ARFID. We propose an efficient genomic analysis of ARFID, by leveraging EDGI operations and resources to conduct the first genome-wide association study (GWAS) of ARFID. Moreover, by combining ARFID with EDGI, we will achieve a complete explication of the DSM-5 feeding and eating disorders chapter. Conceptually, our proposal will test whether ARFID shares a core set of genetic factors with other eating disorders yet is differentiated by a set of disorder-specific genetic factors. Using an efficient and economical approach, ARFID-GEN will: (Aim 1) collect 5,000 ARFID cases and 1,000 new child controls with phenotype and genotype information; (Aim 2) conduct the first GWAS of ARFID plus a standard set of post-GWAS analyses in order to reveal the genetic architecture of ARFID; (Aim 3) apply advanced analytic strategies to explicate the common and divergent genomic architecture of ARFID and the other eating disorders; and (Aim 4) explore the genomic relation among ARFID and multiple psychiatric, metabolic, and anthropometric traits. Launching ARFID-GEN now is the next logical step in eating disorder genomics. Our team has been at the forefront of eating disorder genetics research. Deliverables of the proposed specific aims include: (a) Analysis-ready deep phenotypic and genotypic datasets from the largest ARFID collection in the word; (b) ARFID GWAS; (c) defining the genetic relation of ARFID with other eating disorders; (d) genetic assessment of ARFID’s relation to other phenotypes, informing and refining etiology. The proposed aims will not only reveal the underlying genomic architecture of ARFID, but combined with other ongoing studies and existing data, fully explicate the feeding and eating disorders chapter of the DSM-5, affording the development of a genetically-informed nosology. Given pharmacological treatments for all eating disorders are lacking, we will have created a complete map of the genomics of ARFID, and the eating disorders, that will open avenues for pharmacogenomics and the repurposing and development of medications that target disease biology.