Suicide Epigenetics

描述(由申请人提供)：自杀行为是一种复杂的表型，包括自杀未遂和自杀未遂。家庭、双胞胎和收养研究提供了强有力的证据，证明自杀行为是可遗传的组成部分。这种遗传性似乎部分依赖于精神障碍的存在，如双相情感障碍、抑郁症和酗酒。重要的是，遗传性似乎也在一定程度上独立于它们。我们正在进行的自杀行为遗传学研究已经确定了2p11-12和6q25-26上的连锁区域和2p25上的一个全基因组关联信号(p=5.07×10-8)，这些发现可能会导致在理解自杀行为的生物学基础方面取得重要进展。然而，只有在建立了遗传易感变异与其他因素(如个性特征和环境风险因素)的相互作用后，才会出现更全面的情况。环境应激源，如虐待儿童和早年失去父母，已知在引发自杀行为中发挥重要作用，可能是通过与遗传易感性因素的相互作用。最近的工作表明，压力介导的表观遗传控制BDNF，一个与自杀行为有关的基因，提供了表观遗传机制可以中介这种相互作用的分子证据(Tsankova等人，2006年)。这些结果表明，进一步研究自杀者死后大脑的表观遗传修饰，可能会对自杀行为的病因学和病理生理学有新的见解。进行大规模表观遗传学研究的工具刚刚问世，我们位于约翰霍普金斯大学的表观遗传学中心在开发这类工具方面一直处于领先地位，创建了用于全基因组DNA甲基化(DNaM)研究的全面高通量相对甲基化阵列(CHAMAR)方法(Irizarry等人，2008年)。我们现在提议对dNaM进行全基因组评估，使用来自情绪障碍、自杀完成者和对照组的死后大脑的MALM和额叶皮质(BA10)样本。有希望的dNaM区域将使用亚硫酸氢盐焦磷酸测序进行验证，并将筛选经过验证的候选基因在自杀完成者中的差异表达。为了实现这一目标，我们组建了一支出色的研究团队，他们拥有表观遗传学、遗传学、生物统计学和精神病理学方面的专业知识。自杀行为中差异甲基化基因和基因组区域的识别和表征将a)为自杀行为的生物学基础提供新的见解；b)提供新的治疗靶点；以及c)提供产生体内模型所需的数据，在其中测试治疗靶点。这些对自杀发病机制的新见解可能允许我们在减少这种毁灭性表型的全球负担方面取得显著进展。

DESCRIPTION (provided by applicant): Suicidal behavior is a complex phenotype that includes both attempted and completed suicide. Family, twin, and adoption studies provide strong evidence for a heritable component to suicidal behavior. This heritability appears to be partly dependent on the presence of psychiatric disorders such as bipolar disorder, depression, and alcoholism. Importantly, the heritability also appears to be partly independent of them. Our ongoing studies on the genetics of suicidal behavior have identified linkage regions on 2p11-12 and 6q25-26 and one genome-wide association signal on 2p25 (p=5.07 X 10-8), findings that may lead to important advances in understanding the biological basis underlying suicidal behavior. However, a fuller picture will only emerge as the interaction of genetic susceptibility variants with other factors, such as personality traits and environmental risk factors, are established. Environmental stressors, such as child abuse and early parental loss, are known to play important roles in triggering suicidal behavior, likely through interaction with genetic vulnerability factors. Recent work showing stress-mediated epigenetic control of BDNF, a gene implicated in suicidal behavior, provides molecular evidence that epigenetic mechanisms can mediate this interaction (Tsankova et al., 2006). These results suggest the possibility that new insights into the etiology and pathophysiology of suicidal behavior can be gleaned from further study of epigenetic modifications in post-mortem brains of suicide completers. The tools to perform large-scale epigenetic studies have only just become available, and our Epigenetics Center at Johns Hopkins has been a leader in the development of such tools, having created the Comprehensive High-throughput Arrays for Relative Methylation (CHARM) method for genome-wide DNA methylation (DNAm) studies (Irizarry et al., 2008). We are now proposing to conduct a genome-wide assessment of DNAm using CHARM and samples from the frontal cortex (BA10) of post-mortem brains taken from mood disorder suicide completers and controls. Promising DNAm regions will then be validated using bisulfite pyrosequencing, and validated candidate genes will be screened for differential expression in suicide completers. To accomplish this, we have assembled an outstanding team of investigators with expertise in epigenetics, genetics, biostatistics, and psychopathology. The identification and characterization of differentially methylated genes and genomic regions in suicidal behavior would a) provide new insights into the biological basis of suicidal behavior; b) provide new therapeutic targets; and c) provide the data needed to generate in vivo models in which to test therapeutic targets. These new insights into suicide pathogenesis might allow for dramatic advances in our ability to reduce the global burden of this devastating phenotype.