Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia 23298-0126, USA.
Biol Psychiatry. 2011 Nov 1;70(9):888-96. doi: 10.1016/j.biopsych.2011.07.012. Epub 2011 Aug 25.
Anxiety disorders are common psychiatric conditions that are highly comorbid with each other and related phenotypes such as depression, likely due to a shared genetic basis. Fear-related behaviors in mice have long been investigated as potential models of anxiety disorders, making integration of information from both murine and human genetic data a powerful strategy for identifying potential susceptibility genes for these conditions.
We combined genome-wide association analysis of fear-related behaviors with strain distribution pattern analysis in heterogeneous stock mice to identify a preliminary list of 52 novel candidate genes. We ranked these according to three complementary sources of prior anxiety-related genetic data: 1) extant linkage and knockout studies in mice, 2) a meta-analysis of human linkage scans, and 3) a preliminary human genome-wide association study. We genotyped tagging single nucleotide polymorphisms covering the nine top-ranked regions in a two-stage association study of 1316 subjects from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders chosen for high or low genetic loading for anxiety-spectrum phenotypes (anxiety disorders, neuroticism, and major depression).
Multiple single nucleotide polymorphisms in the PPARGC1A gene demonstrated association in both stages that survived gene-wise correction for multiple testing.
Integration of genetic data across human and murine studies suggests PPARGC1A as a potential susceptibility gene for anxiety-related disorders.
焦虑症是常见的精神疾病，它们之间以及与抑郁等相关表型高度共病，这可能是由于它们具有共同的遗传基础。长期以来，小鼠的恐惧相关行为一直被作为焦虑症的潜在模型进行研究，这使得整合来自小鼠和人类遗传数据的信息成为鉴定这些疾病潜在易感基因的有效策略。
我们将恐惧相关行为的全基因组关联分析与异质品系小鼠的品系分布模式分析相结合，确定了 52 个新的候选基因的初步列表。我们根据三种互补的先前与焦虑相关的遗传数据来源对这些基因进行排序：1）小鼠的现有连锁和基因敲除研究，2）人类连锁扫描的荟萃分析，以及 3）初步的人类全基因组关联研究。我们对 1316 名来自弗吉尼亚成人双胞胎精神和物质使用障碍研究的个体进行了两阶段关联研究，这些个体根据对焦虑谱表型（焦虑症、神经质和重度抑郁症）具有高或低遗传负荷进行了选择。这些个体的 9 个排名最高的区域的标签单核苷酸多态性进行了基因分型。
在两阶段关联研究中，PPARGC1A 基因中的多个单核苷酸多态性在基因水平上经过多次测试校正后仍然存在关联。
人类和小鼠研究的遗传数据整合表明，PPARGC1A 是与焦虑相关障碍的潜在易感基因。
