Integrative metabolomic characterization of ADHD and asthma comorbidity

ADHD 和哮喘合并症的综合代谢组学特征

• 批准号: 10650374
• 负责人: Su Hee Chu
• 金额: $ 17.82万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10650374
• 关键词: Achievement; Adolescence; Adult; Area; Asthma; Attention deficit hyperactivity disorder; Awareness; Behavior Disorders; Biochemical; Biological; Biological Markers; Child; Childhood; Childhood Asthma; Clinical; Communication; Communities; Complex; Data; Diagnosis; Disease; Doctor of Philosophy; Educational process of instructing; Ensure; Environmental Exposure; Epidemiologist; Epidemiology; Etiology; Formulation; Genetic; Genetic Variation; Goals; Hospitals; Individual; Joints; Libraries; Link; Literature; Longevity; Longitudinal Studies; Machine Learning; Mediating; Mediation; Mediator; Mentored Research Scientist Development Award; Mentors; Mentorship; Metabolic; Metabolic Pathway; Metabolism; Methods; Modeling; Molecular; Multiomic Data; Neurodevelopmental Disorder; Pathway interactions; Patients; Phenotype; Prevalence; Process; Program Development; Prospective Studies; Prospective cohort; Public Health; Reporting; Research; Research Design; Research Personnel; Respiration Disorders; Respiratory Disease; Risk; Specific qualifier value; Sphingolipids; Statistical Methods; System; Techniques; Testing; Training; Tryptophan; Validation; Variant; Vitamin D; Woman; antenatal; asthmatic; asthmatic patient; biological systems; career; career development; cohort; comorbidity; experience; genetic testing; genetic variant; high risk; improved; inattention; insight; medical schools; metabolic phenotype; metabolic profile; metabolomics; method development; multiple omics; novel; predictive modeling; programs; prospective; psychogenetics; research and development; screening; skills; small molecule; statistics; success; theories

PROJECT SUMMARY/ABSTRACT Su H. Chu, PhD, MS is a biostatistician and molecular epidemiologist with strong and substantial commitments to integrative omic research in respiratory and neurodevelopmental disease. Her career objective is to become an independent investigator with expertise in developing and applying novel statistical methods and multiomic network approaches that facilitate mechanistic understanding of the intersection of respiratory and neurodevelopmental disease. This proposal combines Dr. Chu’s extensive training in integrative omic methods development, along with her experience in genetic and metabolomic research, to examine the integrative metabolomic etiology of asthma and attention-deficit/hyperactivity disorder overlap (AAO). A wealth of epidemiological literature has revealed with remarkable consistency that asthmatic patients are at greater risk for ADHD, and vice versa, with a number of longitudinal studies of childhood asthma indicating excess risk of ADHD in adolescence and adulthood. However, no studies have directly interrogated the biological mechanisms by which these conditions may be related. The central hypothesis of this proposal is that childhood asthma and ADHD share both common and distinct dysregulated metabolic processes, some of which may have drivers that are genetic in origin. This will be explored using existing genetic and metabolomic data from the Childhood Asthma Management Program (CAMP), the Vitamin D Antenatal Asthma Reduction Trial (VDAART), and the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC), three large prospective cohorts of children with extensive longitudinal phenotyping and multiple omic data types, by identifying metabolites and metabolic profiles associated with AAO (aim 1), constructing multiomic models and features that characterize dysregulated metabolic processes and their upstream drivers in AAO (aim 2), and validation and replication of all findings (aim 3). As Dr. Chu completes these aims, her career development program will facilitate the achievement of her primary training goals: 1) increase clinical understanding of ADHD and asthma diagnosis and treatment; 2) gain a nuanced understanding of best methods for, and practical experience in, the biological and statistical integration of genetic and metabolomic data; 3) develop skills in machine learning and integrative network methods for multiomic analysis; 4) strengthen current areas of experience to stay on the cutting edge of new analytic and study design techniques; and 5) enhance skills in mentorship, teaching, and the responsible conduct and communication of research. The support of a diverse mentoring team comprised of world experts in the fields of asthma and psychiatric genetics, metabolomics, integrative omics, and statistics, along with her strong quantitative training and the vibrant intellectual community of Harvard Medical School and the Brigham and Women’s Hospital, ensure the success of this proposal. Finally, this research will use state-of-the-art multiomic techniques to lay the initial groundwork for understanding the pathobiology of asthma and ADHD comorbidity, a major and well-established public health concern, from which new research programs will emerge.

项目概要/摘要 Su H. Chu，博士，硕士是一位生物统计学家和分子流行病学家，具有坚定而实质性的承诺 她的职业目标是成为呼吸和神经发育疾病的综合组学研究。 独立调查员，在开发和应用新的统计方法和多组学方面具有专业知识 促进对呼吸和呼吸交叉点的机械理解的网络方法 该提案结合了 Chu 博士在综合组学方法方面的广泛培训。 的发展，以及她在遗传和代谢组学研究方面的经验，以检查综合 哮喘的代谢组学病因与注意力缺陷/多动障碍重叠（AAO）。 流行病学文献一致地表明，哮喘患者面临更大的风险 对于注意力缺陷多动症（ADHD），反之亦然，许多针对儿童哮喘的纵向研究表明，儿童哮喘的风险过高 然而，没有研究直接探讨青春期和成年期的多动症的生物学机制。 该提议的中心假设是儿童哮喘和这些疾病可能存在关联。 ADHD 具有共同和独特的失调代谢过程，其中一些可能具有驱动因素 这将利用童年时期的现有遗传和代谢组学数据进行探索。 哮喘管理计划 (CAMP)、维生素 D 产前哮喘减少试验 (VDAART) 以及 2010 年哥本哈根儿童哮喘前瞻性研究 (COPSAC)，三个大型前瞻性队列 具有广泛纵向表型和多种组学数据类型的儿童，通过识别代谢物和 与 AAO 相关的代谢谱（目标 1），构建多组学模型和特征 AAO 中失调的代谢过程及其上游驱动因素（目标 2），以及验证和复制 当朱博士完成这些目标时，她的职业发展计划将促进所有发现（目标 3）。 实现她的主要培训目标：1) 提高对 ADHD 和哮喘诊断的临床理解 和治疗；2) 深入了解生物学的最佳方法和实践经验。 遗传和代谢组数据的统计整合；3）培养机器学习和整合技能 多组学分析的网络方法；4）加强当前的经验领域，以保持领先地位 新的分析和研究设计技术；5) 提高技能、教学和责任感 研究的进行和交流。由世界专家组成的多元化指导团队的支持。 在哮喘和精神遗传学、代谢组学、综合组学和统计学领域，与她一起 哈佛医学院和布里格姆医学院强大的定量培训以及充满活力的知识界 最后，这项研究将使用最先进的技术。 多组学技术为理解哮喘和多动症的病理学奠定初步基础 合并症是一个重要且已确定的公共卫生问题，新的研究计划将从中出现。

项目成果

Metabolomic profiling reveals extensive adrenal suppression due to inhaled corticosteroid therapy in asthma.

• DOI: 10.1038/s41591-022-01714-5
• 发表时间: 2022-04
• 期刊: NATURE MEDICINE
• 影响因子: 82.9
• 作者: Kachroo, Priyadarshini;Stewart, Isobel D.;Kelly, Rachel S.;Stav, Meryl;Mendez, Kevin;Dahlin, Amber;Soeteman, Djora I.;Chu, Su H.;Huang, Mengna;Cote, Margaret;Knilhtila, Hanna M.;Lee-Sarwar, Kathleen;McGeachie, Michael;Wang, Alberta;Wu, Ann Chen;Virkud, Yamini;Zhang, Pei;Wareham, Nicholas J.;Karlson, Elizabeth W.;Wheelock, Craig E.;Clish, Clary;Weiss, Scott T.;Langenberg, Claudia;Lasky-Su, Jessica A.
• 通讯作者: Lasky-Su, Jessica A.

Low gestational vitamin D level and childhood asthma are related to impaired lung function in high-risk children.

妊娠期维生素 D 水平低和儿童哮喘与高危儿童的肺功能受损有关。

• DOI: 10.1016/j.jaci.2020.12.647
• 发表时间: 2021-07
• 期刊: The Journal of allergy and clinical immunology
• 作者: Knihtilä HM;Stubbs BJ;Carey VJ;Laranjo N;Chu SH;Kelly RS;Zeiger RS;Bacharier LB;O'Connor GT;Lasky-Su J;Weiss ST;Litonjua AA
• 通讯作者: Litonjua AA

Metabolomic signatures of lead exposure in the VA Normative Aging Study.

• DOI: 10.1016/j.envres.2020.110022
• 发表时间: 2020-11
• 期刊: Environmental research
• 影响因子: 8.3
• 作者: Kelly RS;Bayne H;Spiro A 2nd;Vokonas P;Sparrow D;Weiss ST;Schwartz J;Nassan FL;Lee-Sarwar K;Huang M;Kachroo P;Chu SH;Litonjua AA;Lasky-Su JA
• 通讯作者: Lasky-Su JA

An independently validated, portable algorithm for the rapid identification of COPD patients using electronic health records.

• DOI: 10.1038/s41598-021-98719-w
• 发表时间: 2021-10-07
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Chu SH;Wan ES;Cho MH;Goryachev S;Gainer V;Linneman J;Scotty EJ;Hebbring SJ;Murphy S;Lasky-Su J;Weiss ST;Smoller JW;Karlson E
• 通讯作者: Karlson E

Genetic Associations and Architecture of Asthma-COPD Overlap.

• DOI: 10.1016/j.chest.2021.12.674
• 发表时间: 2022-05
• 期刊: CHEST
• 影响因子: 9.6
• 作者: John, Catherine;Guyatt, Anna L.;Shrine, Nick;Packer, Richard;Olafsdottir, Thorunn A.;Liu, Jiangyuan;Hayden, Lystra P.;Chu, Su H.;Koskela, Jukka T.;Luan, Jian'an;Li, Xingnan;Terzikhan, Natalie;Xu, Hanfei;Bartz, Traci M.;Petersen, Hans;Leng, Shuguang;Belinsky, Steven A.;Cepelis, Aivaras;Cordero, Ana I. Hernandez;Obeidat, Ma'en;Thorleifsson, Gudmar;Meyers, Deborah A.;Bleecker, Eugene R.;Sakoda, Lori C.;Iribarren, Carlos;Tesfaigzi, Yohannes;Gharib, Sina A.;Dupuis, Josee;Brusselle, Guy;Lahousse, Lies;Ortega, Victor E.;Jonsdottir, Ingileif;Sin, Don D.;Bosse, Yohan;van den Berge, Maarten;Nickle, David;Quint, Jennifer K.;Sayers, Ian;Hall, Ian P.;Langenberg, Claudia;Ripatti, Samuli;Laitinen, Tarja;Wu, Ann C.;Lasky-Su, Jessica;Bakke, Per;Gulsvik, Amund;Hersh, Craig P.;Hayward, Caroline;Langhammer, Arnulf;Brumpton, Ben;Stefansson, Kari;Cho, Michael H.;Wain, Louise, V;Tobin, Martin D.
• 通讯作者: Tobin, Martin D.