Meta-analysis of genome-wide association studies of anxiety disorders.
Meta-analysis of genome-wide association studies of anxiety disorders.
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DOI：
10.1038/mp.2015.197
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发表时间：
2016-10
影响因子：
11
通讯作者：
Hettema JM
中科院分区：
文献类型：
--
作者：
Otowa T;Hek K;Lee M;Byrne EM;Mirza SS;Nivard MG;Bigdeli T;Aggen SH;Adkins D;Wolen A;Fanous A;Keller MC;Castelao E;Kutalik Z;Van der Auwera S;Homuth G;Nauck M;Teumer A;Milaneschi Y;Hottenga JJ;Direk N;Hofman A;Uitterlinden A;Mulder CL;Henders AK;Medland SE;Gordon S;Heath AC;Madden PA;Pergadia ML;van der Most PJ;Nolte IM;van Oort FV;Hartman CA;Oldehinkel AJ;Preisig M;Grabe HJ;Middeldorp CM;Penninx BW;Boomsma D;Martin NG;Montgomery G;Maher BS;van den Oord EJ;Wray NR;Tiemeier H;Hettema JM
焦虑症，即广泛性焦虑症、恐慌症和恐惧症，是常见的、病因复杂的疾病，部分具有遗传基础。尽管基于临床表现的诊断定义不同，焦虑症可能代表基本威胁反应系统的异常调节的潜在共同素质的各种表达。我们对来自7项大型独立研究的9个欧洲血统样本进行了全基因组关联分析。为了识别导致基于访谈生成的DSM的焦虑症之间共享的遗传易感性的遗传变异，我们应用了两种表型方法：（1）分类焦虑症病例和超正常对照之间的比较，以及（2）来自多变量分析的定量表型因子评分，该分析结合了临床表型的信息。我们分别使用逻辑回归和线性回归分析这些表型与全基因组单核苷酸多态性之间的关联。对超过18000名无关个体的9个样本的每种表型组合结果进行荟萃分析。每个荟萃分析确定了一个不同的全基因组显著性区域，以下标记显示出最强的关联：对于病例对照对比，rs 1709393位于染色体带3q12.3上的未表征的非编码RNA位点（P=1.65×10−8）;对于因子得分，CAMKMT内的rs 1067327编码染色体带2 p21上的钙调素-赖氨酸N-甲基转移酶（P=2.86×10−9）。需要对这些发现进行独立复制和进一步探索，以更全面地了解这些变异在焦虑症风险和表达中的作用。
Anxiety disorders, namely generalized anxiety disorder, panic disorder, and phobias, are common, etiologically complex conditions with a partially genetic basis. Despite differing on diagnostic definitions based upon clinical presentation, anxiety disorders likely represent various expressions of an underlying common diathesis of abnormal regulation of basic threat-response systems. We conducted genome-wide association analyses in nine samples of European ancestry from seven large, independent studies. To identify genetic variants contributing to genetic susceptibility shared across interview-generated DSM-based anxiety disorders, we applied two phenotypic approaches: (1) comparisons between categorical anxiety disorder cases and super-normal controls, and (2) quantitative phenotypic factor scores derived from a multivariate analysis combining information across the clinical phenotypes. We used logistic and linear regression, respectively, to analyze the association between these phenotypes and genome-wide single nucleotide polymorphisms. Meta-analysis for each phenotype combined results across the nine samples for over 18 000 unrelated individuals. Each meta-analysis identified a different genome-wide significant region, with the following markers showing the strongest association: for case-control contrasts, rs1709393 located in an uncharacterized non-coding RNA locus on chromosomal band 3q12.3 (P=1.65×10−8); for factor scores, rs1067327 within CAMKMT encoding the calmodulin-lysine N-methyltransferase on chromosomal band 2p21 (P=2.86×10−9). Independent replication and further exploration of these findings are needed to more fully understand the role of these variants in risk and expression of anxiety disorders.