Research Project 2 - Genomic Approaches to Pollutome Effects on Risk of Major Depression in Hispanic Pedigrees

研究项目 2 - 污染组学方法对西班牙裔谱系中重度抑郁症风险的影响

• 批准号: 10749788
• 负责人: John Blangero
• 金额: $ 106.46万
• 依托单位: UNIVERSITY OF TEXAS RIO GRANDE VALLEY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-18 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10749788
• 关键词: Affect; Age; Air Pollutants; Aromatic Polycyclic Hydrocarbons; Arthritis; Behavior; Characteristics; Chemicals; Clinical; Cohort Studies; Data; Depressed mood; Detection; Diabetes Mellitus; Diagnosis; Dioxins; Disease; Economic Burden; Environment; Environmental Epidemiology; Environmental Exposure; Environmental Pollutants; Environmental Risk Factor; Ethnic Origin; Etiology; Exposure to; Family; Family Study; Feeling; Fostering; Furans; Genetic; Genome; Genomic approach; Genomics; Genotype; Heritability; Hispanic; Human; Immigration; Individual; Infectious Agent; Life; Life Style; Major Depressive Disorder; Measures; Mental Depression; Mental disorders; Metals; Mexican Americans; Modification; Nutrient; Persons; Pesticides; Pharmaceutical Preparations; Phenotype; Plasma; Polychlorinated Biphenyls; Predisposing Factor; Prevention; Process; Protocols documentation; Recurrence; Research; Research Project Grants; Resources; Risk; Risk Factors; Sampling; Signal Transduction; Socioeconomic Status; Standardization; Stimulus; Stressful Event; Testing; Time; Toxin; Triazines; Variant; addiction; cohort; cost; design; dietary; disorder risk; genetic information; genetic pedigree; genome sequencing; genome-wide analysis; genomic locus; genomic tools; improved; insight; interest; member; novel; organochlorine pesticide; persistent organic pollutants; pollutant; polybrominated diphenyl ether; response; sex; social stressor; student training; treatment response; whole genome

SUMMARY Major depressive disorder (MDD) is characterized by an extended episode of a persistent feeling of sadness or a lack of interest in outside stimuli. It is among the most common mental illnesses, affecting 16.2% of individuals in the US during their lifetime. MDD is a heterogeneous disorder with a variable clinical course, an inconsistent response to treatment, and little established etiology. Arguably, our lack of understanding of the causes of the disorder hinders improvements in prevention, diagnosis, and treatment. Multiple risk factors predispose MDD, including demographic characteristics (e.g., sex, age, and ethnicity), behavior and lifestyle-related modifications (e.g., addiction, socioeconomic status, immigration status, stressful life events), and both endogenous (e.g., infectious agents) and exogenous environmental factors (e.g., exposure to pollutants/contaminants/toxins). In addition, MDD risk is substantially heritable. However, our ability to identify novel environmental risk factors has been limited by a lack of sufficiently broad environmental measures. Recently, evidence has been accumulating that exposure to pollutants influences the risk of MDD, although most studies have employed indirect exposure estimates. Here we propose to measure person-specific levels of organic and inorganic pollutants to search for environmental determinants of recurrent MDD (rMDD) risk in large multigenerational pedigrees from the Mexican American Family Study (MAFS). A wealth of phenotypic and genetic information exists on the members of the randomly ascertained families in this cohort. Specifically, we previously documented high rates of depression in these families, estimated the heritability of rMDD (h2=0.46), and localized genetic loci using linkage and whole genome sequencing (WGS) approaches. Recently, we developed a novel family-based approach to control for genetic factors and thereby increase the power to detect causal environmental signals influencing disease risk. This analytic approach makes it possible to optimally detect novel environmentally driven determinants of rMDD risk. Given the pedigree-based design and preexisting phenotypic and WGS data, the MAFS cohort provides a powerful efficient resource for studying environmental components of rMDD risk and will provide important new insights into the etiology/mechanisms of MDD risk. Our specific aims are: 1) to obtain individual-level direct measures of the pollutome including a set of 72 persistent organic pollutants and 28 metals in banked plasma samples from two time points and indirect spatially-imputed measures of air pollutant exposure; 2) to detect the influence of pollutants on rMDD risk using a novel statistical approach to control for the effect of genetic factors to maximize environmental pollutant signals; 3) to detect genotype×pollutome interactions in rMDD risk; and 4) to replicate results in an independent set of 750 Mexican American individuals from the Rio Grande Valley Family Study using similar protocols to that of the MAFS. Overall, our project proposes to use genomic tools in a novel way to enhance the identification of environmental risk factors and to foster the study of human genotype×environment interaction. The study also will provide an exciting resource for training students in the value of genomics for environmental epidemiology.

摘要 严重抑郁障碍(MDD)的特征是持续的悲伤或 对外界刺激缺乏兴趣。它是最常见的精神疾病之一，影响16.2%的人 在他们有生之年在美国。MDD是一种异质性疾病，具有不同的临床病程，不一致 对治疗有反应，几乎没有确定的病因。可以说，我们对经济衰退的原因缺乏了解 障碍阻碍了预防、诊断和治疗方面的改进。 多种风险因素易患MDD，包括人口统计特征(如性别、年龄和种族)， 与行为和生活方式相关的改变(例如，上瘾、社会经济地位、移民地位、压力 生活事件)，以及内源性(例如，感染源)和外源性环境因素(例如，暴露 对污染物/污染物/毒素)。此外，MDD风险基本上是可遗传的。然而，我们识别的能力 新的环境风险因素由于缺乏足够广泛的环境措施而受到限制。 最近，越来越多的证据表明，接触污染物会影响MDD的风险，尽管大多数 研究采用了间接暴露估计。在这里，我们建议测量特定于个人的 有机和无机污染物在大范围寻找复发MDD(RMDD)风险的环境决定因素 来自墨西哥裔美国人家庭研究(MAFS)的多代家系。丰富的表型和 遗传信息存在于这个队列中随机确定的家庭成员中。具体来说，我们 以前记录的这些家庭中抑郁症的高比率，估计了rMDD的遗传度(h2=0.46)， 并使用连锁和全基因组测序(WGS)方法定位遗传位点。最近，我们 开发了一种基于家族的新方法来控制遗传因素，从而提高检测能力 影响疾病风险的因果环境信号。这种分析方法使我们有可能最优地 检测新的环境驱动的rMDD风险决定因素。考虑到基于谱系的设计和先前存在的 根据表型和WGS数据，MAFS队列为环境研究提供了一个强大而有效的资源 并将对MDD风险的病因学/机制提供重要的新见解。我们的 具体目标是：1)获得个人层面的直接污染指标，包括一套72项持久性指标 两个时间点的血浆样品中有机污染物和28种金属的间接空间归算 空气污染物暴露的测量；2)使用一种新的统计方法来检测污染物对rMDD风险的影响 控制遗传因素影响最大化环境污染物信号的方法；3)检测 基因×污染组交互作用在rMDD风险中的作用；以及4)在750名墨西哥人的独立组中复制结果 来自里奥格兰德河谷家庭的美国人使用与MAFS相似的方案进行研究。 总体而言，我们的项目建议以一种新的方式使用基因组工具来增强对环境的识别 并促进人类基因×环境交互作用的研究。这项研究还将提供一个 为培训学生认识基因组学对环境流行病学的价值提供了令人兴奋的资源。