Investigating the Genomic Architecture of Anxiety and Overlap with Mental Health Disorders in the Million Veteran Program.

项目总结/摘要 焦虑症在个人层面上造成重大痛苦，成本> 每年仅在美国就有400亿美元。它们是常见的，具有生命周期 估计患病率为28.8%。这些疾病通常与以下疾病共病： 其他精神疾病，如重度抑郁症（MDD）和创伤后应激障碍 PTSD（PTSD）。这些疾病可能在潜在的遗传学上有共同之处， 影响疾病风险的结构。超过90%的患者 广泛性焦虑症（GAD）与其他精神疾病共病 诊断。创伤后应激障碍，有时被认为是一种焦虑症，已经在20- 一年纵向退伍军人队列更常见地患有焦虑症 和/或抑郁症而不是单独诊断。高达90%的PTSD患者可能 患有焦虑症我们建议研究潜在的基因 焦虑症的结构以及它们如何重叠，相互作用和影响其他 共病性疾病我们将在100万个国家进行全基因组关联研究。 退伍军人计划样本（约200，000个信息丰富的个人和不断增长），英国生物银行 （约100，000人）和我们所有人（约36，000信息量大的人，并且还在增长） 使用焦虑特质来研究焦虑症的遗传结构。我们将 进行性别和祖先分层以及联合分析，以搜索性别或 祖先特有的变异性染色体关联研究将是 在相同的样品中进行。性染色体（和线粒体DNA）是 遗传学研究不足，大多数研究集中在常染色体上。这是尽管 多胺系统在抑郁症、应激障碍和自杀中作用的证据 以及多胺催化剂中限速酶的基因， “精脒/精胺N1-乙酰转移酶1”（SAT 1）存在于X染色体上。 包括性染色体对于完整的遗传图谱是至关重要的。 疾病的结构。最后，我们将寻求使用功能基因组学，多基因风险 评分和因果推理，以分析铅发现的功能重要性， 遗传重叠和相关性状的易感性，以及临床翻译的潜力， 调查结果。

Project Summary/Abstract Anxiety disorders cause significant distress on a personal level, and cost > $40,000,000,000 annually in the United States alone. They are common, with lifetime prevalence estimated at about 28.8%. These disorders are frequently co-morbid with other psychiatric disorders such as major depression (MDD) and post-traumatic stress disorder (PTSD). These disorders may share commonalities in the underlying genetic architecture that influences the risk for disease. More than 90% of patients with generalized anxiety disorder (GAD) present with additional comorbid psychiatric diagnoses. PTSD, sometimes considered an anxiety disorder, has been shown in a 20- year longitudinal cohort of veterans to present more commonly as comorbid with anxiety and/or depression than as a lone diagnosis. Up to 90% of individuals with PTSD may present with comorbid anxiety disorders. We propose to study the underlying genetic architecture of anxiety disorders and how they overlap, interact with and influence other co-morbid disorders. We will perform genome-wide association studies in the Million Veteran Program sample (~200,000 informative individuals and growing), UK Biobank (~100,000 individuals), and All of Us (~36,000 informative individuals and growing) using anxiety traits to investigate the genetic architecture of anxiety disorders. We will perform sex and ancestry stratified as well as joint-analyses to search for sex or ancestry specific variation. Sex-chromosome-wide association studies will be conducted in the same samples. The sex chromosomes (and mitochondrial DNA) are understudied in genetics, with most studies focused on the autosomes. This is despite evidence for a role for the polyamine system in depression, stress disorders and suicide and the gene for the rate-limiting enzyme in polyamine catabolism, “spermidine/spermine N1-acetyltransferase 1” (SAT1) being found the X-chromosome. It is critical to include the sex-chromosomes for a complete picture of the genetic architecture of disease. Finally, we will seek to use functional genomics, polygenic risk scoring, and causal inference to assay the functional importance of lead findings, genetic overlap and liability to related traits, and potential for clinical translation of findings.