Genetic Architecture of Avoidant/Restrictive Food Intake Disorder

项目摘要 我们建议通过进行第一次研究， 回避型/限制性食物摄入障碍（ARFID）的基因组研究：ARFID-GEN。ARFID，首次被列入 2013年DSM-5喂养和进食障碍章节的特点是避免或限制食物， 三种不相互排斥的表现（1）恐惧回避，（2）感觉敏感，或（3）不感兴趣/低 胃口关于ARFID的风险机制和病理生理学知之甚少，也没有遗传学研究 迄今为止进行的。正在进行的是饮食失调遗传倡议（EDGI; R 01 MH 120170），旨在 进一步发现饮食失调的基因组：神经性厌食症、神经性贪食症和暴食症 disorder.缺乏EDGI是严重的，征税，并可能危及生命的ARFID。我们提出了一个 ARFID的有效基因组分析，通过利用EDGI的业务和资源进行第一次 ARFID的全基因组关联研究（GWAS）。此外，通过结合ARFID和EDGI，我们将实现 DSM-5喂养和进食障碍章节的完整解释。从概念上讲，我们的建议将测试 ARFID是否与其他饮食失调症共享一组核心遗传因素， 疾病特异性遗传因素。 ARFID-GEN将采用有效和经济的方法：（目标1）收集5，000个ARFID病例， 具有表型和基因型信息的新的儿童对照;（目标2）进行ARFID的第一个GWAS加上 一套标准的GWAS后分析，以揭示ARFID的遗传结构;（目的3）应用 先进的分析策略，以解释共同和不同的基因组结构的ARFID和 其他进食障碍;以及（目的4）探索ARFID与多种精神病， 代谢和人体测量特征。现在推出ARFID-GEN是饮食失调的下一个合乎逻辑的步骤 基因组学 我们的团队一直处于饮食失调遗传学研究的最前沿。建议的具体 目标包括：（a）来自非洲最大的ARFID收集的可供分析的深层表型和基因型数据集， （B）ARFID GWAS;（c）定义ARFID与其他饮食失调的遗传关系;（d）遗传 评估ARFID与其他表型的关系，告知和细化病因。拟议的目标将 不仅揭示了ARFID的潜在基因组结构，而且结合其他正在进行的研究， 现有的数据，充分阐述了DSM-5的喂养和进食障碍章节，提供了发展 基因疾病分类学由于缺乏对所有饮食失调症的药物治疗，我们 将创建一个完整的ARFID基因组图谱，以及饮食失调， 用于药物基因组学以及针对疾病生物学的药物的再利用和开发。

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.