Genetic Architecture of Avoidant/Restrictive Food Intake Disorder

项目摘要 我们建议通过开展第一项研究来加速我们对饮食失调生物学的理解。 回避性/限制性食物摄入障碍(ARFID)的基因组研究：ARFID-GenARFID，最先包含在 DSM-5 2013年的喂养和饮食障碍章节，其特点是由于以下原因而避免或限制食物 三种不相互排斥的陈述(1)恐惧回避，(2)感官敏感，或(3)不感兴趣/低 胃口。对ARFID的风险机制和病理生理学知之甚少，也没有遗传学研究 到目前为止已经进行了一次。正在进行的是饮食障碍遗传倡议(EDGI；R01MH120170)，旨在 进一步的饮食障碍的基因组发现：神经性厌食症、神经性暴食症和暴饮暴食 无序。EDGI缺席的是严重的、繁重的、可能危及生命的ARFID。我们提出了一个 通过利用EDGI操作和资源进行第一次有效的ARFID基因组分析 ARFID全基因组关联研究。此外，通过将ARFID与EDGI相结合，我们将实现 一个完整的DSM-5喂养和饮食失调章节的解释。从概念上讲，我们的提案将测试 ARFID是否与其他饮食障碍共享一组核心遗传因素，但通过一组 疾病特有的遗传因素。 使用高效和经济的方法，ARFID-Gen将：(目标1)收集5,000个ARFID病例和1,000个 提供表型和基因信息的新的儿童对照；(目标2)开展ARFID的第一次全球儿童健康评估，并进行 为揭示ARFID的遗传结构而进行的一套标准的GWAS后分析；(目标3)适用 先进的分析策略来解释ARFID的共同和不同的基因组结构 其他饮食障碍；以及(目标4)探索ARFID和多种精神疾病之间的基因组关系， 新陈代谢和人体测量特征。现在推出ARFID-Gen是治疗进食障碍的下一个合乎逻辑的步骤 基因组学。 我们的团队一直处于进食障碍遗传学研究的前沿。建议的具体项目的交付成果 目标包括：(A)来自#年最大的ARFID收集的可供分析的深层表型和基因型数据集 定义ARFID与其他饮食障碍的遗传关系；(D)遗传 评估ARFID与其他表型的关系，告知和改进病因学。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和 现有数据，充分阐述了DSM-5中关于喂养和饮食失调的章节，为开发提供了依据 一种遗传病因学。鉴于缺乏针对所有饮食失调的药物治疗，我们 将创建一张完整的ARFID基因组学地图，以及饮食失调，这将打开 用于药物基因组学以及针对疾病生物学的药物的重新用途和开发。

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.