Eating Disorders Genetics Initiative (EDGI)

饮食失调遗传学倡议 (EDGI)

• 批准号: 10425368
• 负责人: CYNTHIA M BULIK
• 金额: $ 128.33万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-11 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10425368
• 关键词: Affect; Anorexia Nervosa; Australia; Beds; Behavior; Behavior Disorders; Binge Eating; Binge eating disorder; Biology; Birth; Body mass index; Bulimia; Clinical; Data; Data Set; Denmark; Deposition; Desire for food; Dimensions; Disease; Eating Disorders; Environment; Environmental Risk Factor; Epidemiology; Etiology; Foundations; Funding; Genes; Genetic; Genetic Diseases; Genetic Predisposition to Disease; Genetic Risk; Genetic study; Genomics; Genotype; Goals; Heritability; Heterogeneity; Individual; Joints; Legal; Link; Mendelian randomization; Mental disorders; Meta-Analysis; Metabolic; Metabolic Diseases; Modeling; Morbidity - disease rate; National Institute of Mental Health; Nature; New Zealand; Outcome; Participant; Personality; Phenotype; Physical activity; Polygenic Traits; Population Registers; Psychopathology; Quality of life; Recontacts; Records; Research; Risk; Sampling; Shapes; Testing; Therapeutic; Treatment outcome; Vomiting; Work; advanced analytics; base; comorbidity; disorder risk; excessive exercise; genetic analysis; genetic architecture; genetic association; genome wide association study; genome-wide; health care service utilization; improved; insight; mortality; pleiotropism; psychiatric comorbidity; psychiatric genomics; recruit; statistics; trait; treatment response; working group

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.

项目概要 我们提出饮食失调遗传学计划 (EDGI)，以快速有效地推进基因组研究 三种主要饮食失调 (ED) 的发现 [AN（神经性厌食症）、BN（神经性贪食症）和 BED（暴食症）]。我们提出了一个可测试的 ED 概念，将其视为由共同遗传引起的 易受核心特征（例如食欲失调）的影响，该特征在临床表现中进一步区分 AN、BN 和/或 BED 的不同遗传易感性对维度 ED 行为（例如暴饮暴食、 呕吐、过度运动）、BMI、性格、共病精神病理学、体力活动和代谢 特征。我们认为，这种遗传风险的调色板进一步受到影响的环境因素的影响 ED 的出现、过程和结果。 EDGI 将根据经验测试并完善该模型。重要的是，我们 将确定反映已知的 ED 流行病学分布的不同祖先病例。 使用有效的在线确定方法，EDGI 将：（目标 1）获得深度表型分析 约 4000 人的疾病、共存精神疾病、治疗反应、医疗保健利用率和生活质量 来自美国、澳大利亚 (AUS) 和新西兰的神经性厌食症遗传学计划 (ANGI) 的参与者 （新西兰）； （目标 2）确定 4500 例新 AN 病例的表型和基因型 [（美国、澳大利亚、新西兰和丹麦（DK； 在国家记录中识别出出生时 PKU 卡的基因型）]；约 5950 十亿病例（美国、澳大利亚、新西兰、丹麦）； 约 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 针对 AN、BN、BED、任何 ED 和组件行为的研究 (GWAS)，并与瑞典语进行外部复制 和冰岛数据，加上一组特定的 GWAS 后分析； （目标 4）应用高级分析策略 测试和完善我们的 ED 病因学模型，以阐明 ED 内的异质性，探索遗传关系 ED 与广泛的精神病学、代谢学、人体测量学、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 ED 基因组学的下一个逻辑步骤。 我们的科学团队最近完成了 ANGI，得出了令人信服的 AN 基因发现，包括 鉴定出 8 个显着位点以及与精神和代谢特征的有趣遗传相关性 强烈表明 AN 是一种代谢精神疾病。 EDGI 将扩展到包括 BN 和 BED。 可交付成果包括： (a) 大型 AN、BN 和 BED 样本的丰富表型和基因型数据； (二) 澄清 ED 之间以及 ED 与其他目标性状之间遗传关系的性质； （能 ED 风险和分化的实证模型； (d) 初步了解基因与环境如何相互作用 在急诊科； (e) 根据现行法律和监管标准以及公开的摘要存放样本和数据 统计数据。我们的最终目标与精神病基因组学联盟 (PGC) 保持一致，提供“可操作的” 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。