Division of Human Genetics. University of Cape Town. Cape Town. South Africa.
Imaging Genetics Center. Mark and Mary Neuroimaging & Informatics Institute. Keck School of Medicine of the University of Southern California. Marina del Rey, CA. USA.
J Affect Disord. 2019 Feb 15;245:885-896. doi: 10.1016/j.jad.2018.11.082. Epub 2018 Nov 13.
There have been considerable recent advances in understanding the genetic architecture of anxiety disorders and posttraumatic stress disorder (PTSD), as well as the underlying neurocircuitry of these disorders. However, there is little work on the concordance of genetic variations that increase risk for these conditions, and that influence subcortical brain structures. We undertook a genome-wide investigation of the overlap between the genetic influences from single nucleotide polymorphisms (SNPs) on volumes of subcortical brain structures and genetic risk for anxiety disorders and PTSD.
We obtained summary statistics of genome-wide association studies (GWAS) of anxiety disorders (N= 7016, N= 14,745), PTSD (European sample; N= 2424, N= 7113) and of subcortical brain structures (N = 13,171). SNP Effect Concordance Analysis (SECA) and Linkage Disequilibrium (LD) Score Regression were used to examine genetic pleiotropy, concordance, and genome-wide correlations respectively. SECAs conditional false discovery was used to identify specific risk variants associated with anxiety disorders or PTSD when conditioning on brain related traits.
For anxiety disorders, we found evidence of significant concordance between increased anxiety risk variants and variants associated with smaller amygdala volume. Further, by conditioning on brain volume GWAS, we identified novel variants that associate with smaller brain volumes and increase risk for disorders: rs56242606 was found to increase risk for anxiety disorders, while two variants (rs6470292 and rs683250) increase risk for PTSD, when conditioning on the GWAS of putamen volume.
Despite using the largest available GWAS summary statistics, the analyses were limited by sample size.
These preliminary data indicate that there is genome wide concordance between genetic risk factors for anxiety disorders and those for smaller amygdala volume, which is consistent with research that supports the involvement of the amygdala in anxiety disorders. It is notable that a genetic variant that contributes to both reduced putamen volume and PTSD plays a key role in the glutamatergic system. Further work with GWAS summary statistics from larger samples, and a more extensive look at the genetics underlying brain circuits, is needed to fully delineate the genetic architecture of these disorders and their underlying neurocircuitry.
近年来，人们对焦虑症和创伤后应激障碍（PTSD）的遗传结构，以及这些疾病的潜在神经回路有了更深入的了解。然而，关于增加这些疾病风险的遗传变异的一致性，以及影响皮质下脑结构的遗传变异的研究还很少。我们对皮质下脑结构体积的单核苷酸多态性（SNP）遗传影响与焦虑症和 PTSD 的遗传风险之间的重叠进行了全基因组研究。
我们获得了焦虑症（N=7016，N=14745）、PTSD（欧洲样本；N=2424，N=7113）和皮质下脑结构（N=13171）全基因组关联研究（GWAS）的汇总统计数据。SNP 效应一致性分析（SECA）和连锁不平衡（LD）得分回归分别用于检测遗传多效性、一致性和全基因组相关性。SECA 条件假发现用于鉴定与焦虑症或 PTSD 相关的特定风险变异，条件是大脑相关特征。
对于焦虑症，我们发现焦虑风险变异与杏仁核体积较小相关的变异之间存在显著一致性的证据。此外，通过对大脑体积 GWAS 进行条件处理，我们鉴定出了与较小的大脑体积和增加疾病风险相关的新变异：rs56242606 被发现会增加焦虑症的风险，而 rs6470292 和 rs683250 两个变异会增加 PTSD 的风险，条件是对苍白球体积的 GWAS。
尽管使用了最大的可用 GWAS 汇总统计数据，但由于样本量有限，分析受到限制。
这些初步数据表明，焦虑症的遗传风险因素与杏仁核体积较小之间存在全基因组一致性，这与支持杏仁核参与焦虑症的研究结果一致。值得注意的是，一个导致苍白球体积减少和 PTSD 的遗传变异在谷氨酸能系统中起着关键作用。需要使用更大样本的 GWAS 汇总统计数据和更广泛的研究来研究大脑回路的遗传基础，以充分描绘这些疾病的遗传结构及其潜在的神经回路。
