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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.

总结