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.

总结 重度抑郁症（MDD）的特征是持续的悲伤感或抑郁情绪的延长发作。 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 在美国的一生中。MDD是一种异质性疾病，具有可变的临床病程， 对治疗的反应，以及很少确定的病因。可以说，我们缺乏对原因的了解， 疾病阻碍了预防、诊断和治疗的改进。 多种风险因素易患MDD，包括人口统计学特征（例如，性别、年龄和种族）， 行为和生活方式相关的改变（例如，成瘾，社会经济地位，移民身份，压力 生活事件），以及内源性的（例如，感染因子）和外源性环境因素（例如，暴露 污染物/污染物/毒素）。此外，MDD风险在很大程度上是可遗传的。然而，我们识别 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，暴露于污染物会影响MDD的风险，尽管大多数 研究采用了间接接触估计。在这里，我们建议衡量个人的具体水平， 有机和无机污染物，以寻找大规模复发性MDD（rMDD）风险的环境决定因素 墨西哥裔美国人家庭研究（MAFS）。丰富的表型和 在这个队列中随机确定的家庭成员上存在遗传信息。我们特别 先前记录的这些家族中抑郁症的高发病率，估计rMDD的遗传度（h2=0.46）， 以及使用连锁和全基因组测序（WGS）方法定位遗传基因座。最近我们 开发了一种新的以家庭为基础的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。这种分析方法可以最佳地 检测rMDD风险的新环境驱动决定因素。考虑到基于血统的设计和预先存在的 表型和WGS数据，MAFS队列提供了一个强大的有效资源，研究环境 rMDD风险的组成部分，并将提供重要的MDD风险的病因/机制的新见解。我们 具体目标是：1）获得污染物的个人水平的直接测量，包括一组72个持久性 来自两个时间点的库存血浆样本中的有机污染物和28种金属， 空气污染物暴露的措施; 2）使用新的统计方法检测污染物对rMDD风险的影响 控制遗传因素的影响，以最大限度地提高环境污染信号的方法; 3）检测 rMDD风险中的基因型×污染组相互作用;以及4）在一组独立的750名墨西哥人中复制结果 来自格兰德河流域家庭研究的美国个体，使用与MAFS相似的方案。 总的来说，我们的项目建议以一种新的方式使用基因组工具来加强环境中的 风险因素，促进人类基因型×环境相互作用的研究。该研究还将提供一个 这是一个令人兴奋的资源，用于培训学生了解基因组学对环境流行病学的价值。