Mid-Atlantic Mental Illness Research Education and Clinical Center, Durham VAMC, Durham, NC, USA.
Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA.
Transl Psychiatry. 2017 Nov 30;7(11):1265. doi: 10.1038/s41398-017-0021-6.
Depending on the traumatic event, a significant fraction of trauma survivors subsequently develop PTSD. The additional variability in PTSD risk is expected to arise from genetic susceptibility. Unfortunately, several genome-wide association studies (GWAS) have failed to identify a consistent genetic marker for PTSD. The heritability of intermediate phenotypes such as regional brain volumes is often 80% or higher. We conducted a GWAS of subcortical brain volumes in a sample of recent military veteran trauma survivors (n = 157), grouped into PTSD (n = 66) and non-PTSD controls (n = 91). Covariates included PTSD diagnosis, sex, intracranial volume, ancestry, childhood trauma, SNP×PTSD diagnosis, and SNP×childhood trauma. We identified several genetic markers in high linkage disequilibrium (LD) with rs9373240 (p = 2.0 × 10, FDR q = 0.0375) that were associated with caudate volume. We also observed a significant interaction between rs9373240 and childhood trauma (p-values = 0.0007-0.002), whereby increased trauma exposure produced a stronger association between SNPs and increased caudate volume. We identified several SNPs in high LD with rs34043524, which is downstream of the TRAM1L1 gene that were associated with right lateral ventricular volume (p = 1.73 × 10; FDR q = 0.032) and were also associated with lifetime alcohol abuse or dependence (p = 2.49 × 10; FDR q = 0.0375). Finally, we identified several SNPs in high LD with rs13140180 (p = 2.58 × 10; FDR q = .0016), an intergenic region on chromosome 4, and several SNPs in the TMPRSS15 associated with right nucleus accumbens volume (p = 2.58 × 10; FDR q = 0.017). Both TRAM1L1 and TMPRSS15 have been previously implicated in neuronal function. Key results survived genome-wide multiple-testing correction in our sample. Leveraging neuroimaging phenotypes may offer a shortcut, relative to clinical phenotypes, in mapping the genetic architecture and neurobiological pathways of PTSD.
根据创伤事件的不同，相当一部分创伤后应激障碍幸存者随后会发展为 PTSD。PTSD 风险的额外可变性预计将来自遗传易感性。不幸的是，几项全基因组关联研究（GWAS）未能确定 PTSD 的一致遗传标记。区域性脑容量等中间表型的遗传力通常在 80%或更高。我们对一组最近经历过军事创伤的退伍军人创伤后应激障碍幸存者（n=157）进行了亚皮质脑容量的 GWAS 研究，这些幸存者被分为 PTSD 组（n=66）和非 PTSD 对照组（n=91）。协变量包括 PTSD 诊断、性别、颅内体积、祖源、儿童期创伤、SNP×PTSD 诊断和 SNP×儿童期创伤。我们在与 rs9373240 高度连锁不平衡（LD）的几个遗传标记中发现（p=2.0×10，FDR q=0.0375），这些标记与尾状核体积有关。我们还观察到 rs9373240 与儿童期创伤之间存在显著的相互作用（p 值=0.0007-0.002），即随着创伤暴露的增加，SNP 与尾状核体积增加之间的相关性更强。我们在与 rs34043524 高度连锁的几个 SNP 中发现，rs34043524 位于 TRAM1L1 基因下游，与右侧侧脑室体积相关（p=1.73×10；FDR q=0.032），并与终生酒精滥用或依赖相关（p=2.49×10；FDR q=0.0375）。最后，我们在与 rs13140180（p=2.58×10；FDR q=0.0016）高度连锁的几个 SNP 中发现，rs13140180 位于染色体 4 上的一个基因间区域，以及与右侧伏隔核体积相关的几个 SNP（p=2.58×10；FDR q=0.017）。TRAM1L1 和 TMPRSS15 之前都与神经元功能有关。在我们的样本中，关键结果在全基因组多重测试校正后仍然存在。与临床表型相比，利用神经影像学表型可能会在 PTSD 的遗传结构和神经生物学途径的映射方面提供一个捷径。
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