Over 40% of adults are obese in the US. Although reducing caloric intake and/or increasing physical activity can lead to weight loss in the short to medium term in some people, they lose efficacy in the long term. Bariatric surgeries are currently the most durable and effective treatment for obesity but substantial complications have been reported. Pharmaceutical options for treating obesity have been very limited and not efficacious. Anti- obesity medications generally target either central nervous system (CNS) pathways that regulate sensations of satiety and fullness, or peripheral modulators of digestion, metabolism and lipogenesis that result in only modest effects. One of the major challenges in developing anti-obesity medications is that our CNS (i.e., hypothalamus, brainstem, and limbic system), which regulates appetite and food intake, substantially overlaps with those that modulate mood, anxiety and behavior. Several CNS-acting drugs that have been developed to suppress appetite for weight loss have adverse behavioral effects. For example, Rimonabant (endocannabinoid receptor antagonist) and Ecopipam (dopamine receptor antagonist) precipitate severe depression and suicide ideations; and the recent FDA-approved MC4R agonist (Setmelanotide) for individuals carrying pathogenic mutations in POMC, PCSK1 or LEPR genes along the leptin-melanocortin pathway also incurs similar psychiatric effects in 26% patients. All of these highlight safety issues in targeting the CNS for appetite suppression. However, the recent success of glucagon-like peptide-1 receptor (GLP1R) agonists (Liraglutide, Semagglutide, Tirzepatide, etc.) and amylin analogs (Cagrilintide) in treating obesity without apparent CNS-related adverse effects demonstrates the proof of principle that targeting certain parts of our CNS for weight loss can be safe, i.e., targeting specific neural circuits primarily in the brainstem for GLP1R agonists and amylin analogs. It also indicates that a subset of obesity genes can be safely targeted pharmaceutically in the CNS. There has been tremendous progress in genetic studies of obesity and adiposity traits in the past 20 years, especially led by our Genetic Investigation of ANThropometric traits [GIANT] consortium, which has identified >1,700 adiposity loci. These efforts offer an unprecedented opportunity to identify novel drug targets to treat obesity, a field that urgently needs a paradigm shift. By leveraging comprehensive GWAS resources for adiposity, psychiatric traits and addictive risk behaviors, and rich phenome information across large-scale biobanks, we propose to integrate multi-layers of omics to identify obesity genes using whole-exome sequencing, transcriptome-wide and proteome-wide association analyses (Aim 1), predict pharmacological effects upon targeting obesity genes using drug-target Mendelian randomization analyses and gene-based phenome-wide association analyses (Aim 2), and screen neuronal effects of obesity drug targe...