Eating Disorders Genetics Initiative (EDGI)

项目摘要 我们提出饮食失调遗传学倡议（EDGI），以快速，有效地推进基因组 在三种主要的进食障碍（ED）[AN（神经性厌食症），BN（神经性贪食症）， BED（暴食症）。我们提出了一个可测试的概念，ED作为产生于一个共同的遗传 对核心特征的脆弱性（例如，食欲失调），其在临床表现中进一步分化 AN、BN和/或B艾德的遗传易感性不同，导致维度艾德行为（例如，暴饮暴食 呕吐、过度运动）、BMI、个性、共病精神病理学、体力活动和代谢 性状我们认为，这种遗传风险的调色板进一步受到环境因素的影响， EDGI将以实证的方式检验和完善这一模型。重要的是我们 将确定反映已知ED流行病学分布的祖先多样性病例。 使用一种有效的在线确定方法，EDGI将：（目标1）在治疗过程中获得深入的表型分析。 疾病、共病精神疾病、治疗反应、医疗保健利用和生活质量约4000 来自美国、澳大利亚（AUS）和新西兰的神经性厌食症遗传学倡议（ANGI）参与者 (NZ)（2）确定4500例AN新发病例的表型和基因型[（美国、澳大利亚、新西兰和丹麦; 在国家记录中从出生时的PKU卡中鉴定基因型）; ~5950例BN病例（US、AUS、NZ、DK）; ~4050例BED病例（美国、澳大利亚、新西兰）和1500例对照;（目标3）进行预先计划的全基因组关联 AN、BN、B艾德、任何艾德和组件行为的研究（GWAS），外部重复使用瑞典语 和冰岛的数据，加上一组特定的后GWAS分析;（目标4）应用先进的分析策略， 测试和完善我们的ED病因学模型，以解释ED内的异质性，探索遗传关系， ED与一系列精神、代谢、人体测量、身体活动、教育 表型和塑造这些关系的力量，并初步探索多基因风险（PRS）x 环境相互作用。EDGI代表了艾德基因组学的下一个合乎逻辑的步骤。 我们的科学团队最近完成了ANGI，得出了令人信服的AN遗传学发现，包括 鉴定了8个显著的基因座，并与精神和代谢性状有有趣的遗传相关性 强烈提示AN是一种代谢精神障碍。EDGI将扩展到包括BN和BED。 数据包括：（a）大量AN、BN和BED样本的丰富表型和基因型数据;（B） 阐明ED之间以及ED与其他目标性状之间的遗传关系的性质;（c） 艾德风险和分化的经验模型;（d）对基因和环境如何相互作用的初步了解 （e）根据现行法律的和监管标准以及公开摘要提供样本和存款数据 统计我们的最终目标与精神病学基因组学联盟（PGC）保持一致， 这些发现将转化为对ED具有生物学、临床和治疗意义的见解。

Project Summary We propose the Eating Disorders Genetics Initiative (EDGI) to rapidly and efficiently advance genomic discovery across the three major eating disorders (EDs) [AN (anorexia nervosa), BN (bulimia nervosa), and BED (binge-eating disorder)]. We propose a testable conceptualization of EDs as arising from a shared genetic vulnerability to a core trait (e.g., dysregulated appetite) that is further differentiated across clinical presentations of AN, BN, and/or BED by differing genetic predispositions to dimensional ED behaviors (e.g., binge eating, vomiting, excessive exercise), BMI, personality, comorbid psychopathology, physical activity, and metabolic traits. We propose that this palette of genetic risk is further influenced by environmental factors that affect emergence, course, and outcome of the ED. EDGI will empirically test and refine this model. Importantly, we will ascertain ancestrally diverse cases reflecting known epidemiological distributions of EDs. Using an efficient online ascertainment approach, EDGI will: (Aim 1) obtain deep phenotyping on course of illness, comorbid psychiatric conditions, treatment response, healthcare utilization, and quality of life on ~4000 participants in the Anorexia Nervosa Genetics Initiative (ANGI) from the US, Australia (AUS), and New Zealand (NZ); (Aim 2) ascertain, phenotype, and genotype 4500 new AN cases [(US, AUS, NZ, and Denmark (DK; identified in national records an genotypes from PKU cards from birth)]; ~5950 BN cases (US, AUS, NZ, DK); ~4050 BED cases (US, AUS, NZ) and 1500 controls; (Aim 3) conduct pre-planned genome-wide association studies (GWAS) for AN, BN, BED, any ED, and component behaviors, with external replications with Swedish and Icelandic data, plus a specific set of post-GWAS analyses; (Aim 4) apply advanced analytic strategies to test and refine our etiological model of EDs to explicate within-ED heterogeneity, explore the genetic relation between EDs and a broad array of psychiatric, metabolic, anthropometric, physical activity, educational phenotypes and the forces that shape those relationships, and preliminarily explore polygenic risk (PRS) x environmental interactions. EDGI represents the next logical step in ED genomics. Our scientific team recently completed ANGI, yielding compelling genetic findings for AN including the identification of 8 significant loci and intriguing genetic correlations with both psychiatric and metabolic traits strongly suggesting that AN is a metabo-psychiatric disorder. EDGI will expand to include BN and BED. Deliverables include: (a) rich phenotypic and genotypic data on large AN, BN, and BED samples; (b) clarification of the nature of genetic relationship among EDs and between EDs and other target traits; (c) an empirical model of ED risk and differentiation; (d) preliminary insight into how genes and environment interact in EDs; (e) sample and data deposit per current legal and regulatory standards and publicly available summary statistics. Our ultimate goal aligns with the Psychiatric Genomics Consortium (PGC) by delivering “actionable” findings that will be transformable into biologically, clinically, and therapeutically meaningful insights on EDs.