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

基本信息

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
项目类别：
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

项目摘要

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.

概括重度抑郁症 (MDD) 的特点是长期持续的悲伤或对外界刺激缺乏兴趣是最常见的精神疾病之一，影响 16.2% 的人。在美国，MDD 是一种异质性疾病，临床病程各异、不一致。对治疗的反应以及很少确定的病因可以说，我们缺乏对病因的了解。疾病阻碍了预防、诊断和治疗的改进。 MDD 的易感因素有多种，包括人口特征（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（例如传染源）和外源性环境因素（例如暴露）然而，MDD 风险基本上是可遗传的。由于缺乏足够广泛的环境措施，新的环境风险因素受到限制。最近，越来越多的证据表明，接触污染物会影响患 MDD 的风险，尽管大多数人研究采用了间接暴露估计，我们建议测量特定人群的暴露水平。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来自墨西哥美国家庭研究 (MAFS) 的多代谱系丰富的表型和特征。具体而言，我们在该队列中随机确定的家庭成员中存在遗传信息。先前记录的这些家庭的抑郁症发病率很高，估计了 rMDD 的遗传力（h2=0.46），最近，我们使用连锁和全基因组测序（WGS）方法来定位遗传位点。开发了一种新的基于家庭的方法来控制遗传因素，从而提高检测能力这种分析方法可以优化影响疾病风险的因果环境信号。鉴于基于谱系的设计和预先存在的，检测 rMDD 风险的新环境驱动决定因素。表型和 WGS 数据，MAFS 队列为研究环境提供了强大有效的资源 rMDD 风险的组成部分，将为我们的 MDD 风险的病因/机制提供重要的新见解。具体目标是： 1) 获得污染组的个人水平直接测量值，包括一组 72 个持久性测量值两个时间点储存的血浆样本中的有机污染物和 28 种金属以及间接空间插补空气污染物暴露的测量；2) 使用新颖的统计方法检测污染物对 rMDD 风险的影响控制遗传因素影响以最大化环境污染物信号的方法；3) 检测； rMDD 风险中基因型×污染组的相互作用；4) 在 750 名墨西哥人的独立组中复制结果里奥格兰德河谷家庭研究中的美国个体使用与 MAFS 类似的方案。总的来说，我们的项目建议以一种新颖的方式使用基因组工具来增强对环境的识别风险因素并促进人类基因型与环境相互作用的研究。令人兴奋的资源，用于培训学生了解基因组学在环境流行病学中的价值。