OBJECTIVE Anxiety disorders are common and often disabling. The goal of this study was to examine the genetic architecture of anxiety disorders and anxiety symptoms, which are also frequently comorbid with other mental disorders, such as major depressive disorder. METHODS Using one of the world's largest biobanks including genetic, environmental, and medical information, the Million Veteran Program, the authors performed a genome-wide association study (GWAS) of a continuous trait for anxiety (based on score on the Generalized Anxiety Disorder 2-item scale [GAD-2], N=199,611) as the primary analysis and self-report of physician diagnosis of anxiety disorder (N=224,330) as a secondary analysis. RESULTS The authors identified five genome-wide significant signals for European Americans and one for African Americans on GAD-2 score. The strongest were on chromosome 3 (rs4603973) near SATB1, a global regulator of gene expression, and on chromosome 6 (rs6557168) near ESR1, which encodes an estrogen receptor. The locus identified on chromosome 7 (rs56226325, MAF=0.17) near MAD1L1 was previously identified in GWASs of bipolar disorder and schizophrenia. The authors replicated these findings in the summary statistics of two major published GWASs for anxiety, and also found evidence of significant genetic correlation between the GAD-2 score results and previous GWASs for anxiety (rg=0.75), depression (rg=0.81), and neuroticism (rg=0.75). CONCLUSIONS This is the largest GWAS of anxiety traits to date. The authors identified novel genome-wide significant associations near genes involved with global regulation of gene expression (SATB1) and the estrogen receptor alpha (ESR1). Additionally, the authors identified a locus (MAD1L1) that may have implications for genetic vulnerability across several psychiatric disorders. This work provides new insights into genetic risk mechanisms underpinning anxiety and related psychiatric disorders.

中文翻译：

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焦虑的可重复遗传风险位点：来自百万退伍军人计划中约 200,000 名参与者的结果。

目的 焦虑症很常见，而且常常致残。这项研究的目的是检查焦虑症和焦虑症状的遗传结构，这些症状也经常与其他精神障碍（如重度抑郁症）合并。方法 使用世界上最大的生物库之一，包括遗传、环境和医学信息，百万退伍军人计划，作者对焦虑的连续特征进行了全基因组关联研究 (GWAS)（基于广泛性焦虑症 2 -项目量表 [GAD-2]，N=199,611）作为主要分析，医生诊断焦虑症的自我报告（N=224,330）作为次要分析。结果 作者根据 GAD-2 评分确定了欧洲裔美国人的五种全基因组显着信号和非裔美国人的一种。最强的是在SATB1（基因表达的全局调节剂）附近的3号染色体（rs4603973）和ESR1附近的6号染色体（rs6557168）上，后者编码雌激素受体。在 MAD1L1 附近的 7 号染色体（rs56226325，MAF=0.17）上鉴定的基因座先前在双相情感障碍和精神分裂症的 GWAS 中被鉴定。作者在两个主要已发表的焦虑症 GWAS 的汇总统计中重复了这些发现，并且还发现了 GAD-2 评分结果与之前的焦虑症 (rg=0.75)、抑郁症 (rg=0.81)、和神经质（rg=0.75）。结论 这是迄今为止最大的焦虑特征 GWAS。作者确定了与基因表达全局调节 (SATB1) 和雌激素受体 α (ESR1) 相关的基因附近的新型全基因组显着关联。此外，作者确定了一个基因座 (MAD1L1)，该基因座可能对多种精神疾病的遗传脆弱性产生影响。这项工作提供了对支持焦虑和相关精神疾病的遗传风险机制的新见解。