Leveraging Correlated Traits to Identify Genetic Associations with Sleep Disordered Breathing

利用相关特征来识别与睡眠呼吸障碍的遗传关联

• 批准号: 9814425
• 负责人: Tamar Sofer
• 金额: $ 13.43万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9814425
• 关键词: Address; Apnea; Autonomic nervous system; Behavioral; Bioinformatics; Blood Pressure; Cardiopulmonary; Characteristics; Chronic; Clinical; Comorbidity; Complex; Congenital neurologic anomalies; Diagnosis; Diagnostic; Disease; Dyslipidemias; Event; Family Study; Foundations; Framingham Heart Study; Future; Genetic; Genetic study; Genotype; Glucose; Goals; Health; Healthcare; Heritability; Heterogeneity; Hispanic Community Health Study/Study of Latinos; Hypoxemia; Insulin; Insulin Resistance; Iron; Jackson Heart Study; Lipids; Literature; Lung; Lung diseases; Measures; Medical Genetics; Metabolic; Methodology; Methods; Molecular; Morbidity - disease rate; Multi-Ethnic Study of Atherosclerosis; National Heart, Lung, and Blood Institute; Obesity; Obstructive Sleep Apnea; Outcome; Pathway interactions; Patients; Phenotype; Physiological; Polysomnography; Population; Prevalence; Randomized; Reporting; Research; Research Proposals; Respiratory physiology; Risk; Sample Size; Sampling; Sex Differences; Sleep; Sleep Apnea Syndromes; Syndrome; Testing; Waist-Hip Ratio; Woman; base; blood glucose regulation; cardiometabolism; cohort; disorder subtype; genetic analysis; genetic association; genetic variant; heart rate variability; improved; indexing; men; personalized intervention; personalized medicine; pleiotropism; pulmonary function; sex; trait

PROJECT SUMMARY/ABSTRACT Sleep Disordered Breathing (SDB) is a complex disorder that is common in the population and is associated with significant adverse health outcomes. Despite considerable heritability, elucidation of the genetic basis of this disorder has been limited by relatively small samples - due to under diagnosis and under reporting of SDB, and paucity of overnight measurements of SDB traits - and potential heterogeneity. Given that SDB is physiologically and metabolically related to other traits, there is an opportunity to increase power in the relatively-small genetic association studies of SDB traits by leveraging large association studies in correlated traits. Using correlated traits will also be useful for identifying SDB mechanisms captured by these traits, as a first step in explaining, at the genetic level, the heterogeneity of SDB. Therefore, we propose to utilize genetic associations for traits that correlate with SDB to dissect genetically-determined mechanisms of SDB, that are attributable to different molecular/physiological pathways, and are captured by different traits. We will take two approaches. First, we will study the genetic correlations between multiple cardiopulmonary and metabolic traits and SDB traits in the largest cohort with overnight measurements of SDB traits, the Hispanic Community Health Study/Study of Latinos. Based on these correlations, we will identify genetic loci associated with SDB from those that were previously implicated with the correlated traits. Second, we will study and implement approaches based on Polygenic Risk Scores (PRSs) in multiple, diverse, NHLBI cohorts. We will use previously known associations to construct PRSs for the detected correlated traits, and study their association with SDB traits. We will implement causal analyses using recently proposed methodologies of Mendelian Randomization in the presence of pleiotropy to study whether traits such as BMI, blood pressure, dyslipidemia, and insulin resistance are causally associated with SDB. These analyses will reveal specific genetically-determined mechanisms of SDB, setting the foundation for the ultimate goal of identifying subtypes of the disorder and consequently developing personalized therapies

项目总结/摘要 睡眠呼吸障碍（SDB）是一种复杂的疾病，在人群中很常见， 对健康有严重的不良影响尽管有相当大的遗传性，阐明遗传基础， 这种疾病受到相对较小样本的限制-由于诊断不足和报告不足， SDB，缺乏SDB性状和潜在异质性的过夜测量。鉴于深发展是 生理和代谢相关的其他性状，有机会增加权力， SDB性状的相对小的遗传关联研究，通过利用相关的大关联研究， 性状使用相关的特征也将有助于识别由这些特征捕获的SDB机制， 这是在遗传水平上解释SDB异质性的第一步。因此，我们建议利用 与SDB相关的性状的遗传关联，以剖析SDB的遗传决定机制， 这可归因于不同的分子/生理途径，并被不同的性状所捕获。 我们将采取两种方法。首先，我们将研究多个基因之间的遗传相关性。 心肺和代谢性状和SDB性状在最大的队列过夜测量， SDB性状，西班牙裔社区健康研究/拉丁美洲人研究。基于这些相关性，我们将 从先前与相关性状相关的基因座中鉴定与SDB相关的基因座。 其次，我们将研究和实施基于多基因风险评分（PRS）的方法， 不同的NHLBI队列。我们将使用以前已知的关联来构建检测到的 相关性状，并研究其与SDB性状的相关性。我们将使用 最近提出的方法孟德尔随机化的存在多效性，以研究是否 诸如BMI、血压、血脂异常和胰岛素抵抗的特征与SDB有因果关系。 这些分析将揭示SDB的特定遗传决定机制，为 最终目标是确定疾病的亚型，从而开发个性化治疗