Suicide Epigenetics

自杀表观遗传学

• 批准号: 8223587
• 负责人: VIRGINIA L WILLOUR
• 金额: $ 20.66万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8223587
• 关键词: 2p11; 2p25; Adoption; Alcoholism; Algorithms; Biological; Biometry; Bipolar Disorder; Brain; Brain region; Brain-Derived Neurotrophic Factor; Candidate Disease Gene; Cause of Death; Child Abuse; Clinical; Complex; DNA; DNA Methylation; Data; Development; Environmental Risk Factor; Epigenetic Process; Etiology; Family; Functional disorder; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Genome; Genomics; Glean; Heritability; Hybridization Array; Investigation; Lead; Limbic System; Logistic Regressions; Mediating; Mental Depression; Mental disorders; Methods; Methylation; Modification; Molecular; Mood Disorders; Pathogenesis; Pattern; Personality Traits; Phenotype; Play; Psychopathology; Relative (related person); Research Personnel; Risk; Role; Sampling; Signal Transduction; Stress; Suicide; Testing; Twin Multiple Birth; Validation; Variant; Work; accomplished suicide; base; bisulfite; environmental stressor; flexibility; frontal lobe; genome wide association study; genome-wide; in vivo Model; insight; interest; new therapeutic target; novel; research study; suicidal behavior; suicide brain; therapeutic target; tool

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. PUBLIC HEALTH RELEVANCE: Suicidal behavior is perhaps the most dreaded aspect of psychiatric disorders and among the leading causes of death for young people. This application aims to identify epigenetic modifications that increase the risk for suicidal behavior.

描述（由申请人提供）：自杀行为是一种复杂的表型，包括企图自杀和已完成自杀。家庭、双胞胎和收养研究为自杀行为的遗传因素提供了强有力的证据。这种遗传性似乎部分取决于精神疾病的存在，如双相情感障碍、抑郁症和酗酒。重要的是，遗传能力似乎也部分独立于它们。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上的连锁区域以及2p25上的一个全基因组关联信号（p=5.07 X 10-8），这些发现可能会在理解自杀行为背后的生物学基础方面取得重要进展。然而，只有当遗传易感性变异与其他因素（如人格特征和环境风险因素）的相互作用得到确定时，才会出现更全面的情况。众所周知，环境压力因素，如儿童虐待和早期失去父母，在引发自杀行为方面发挥着重要作用，可能与遗传易感性因素相互作用。最近的研究表明应激介导的BDNF（一种与自杀行为有关的基因）的表观遗传控制为表观遗传机制可以调节这种相互作用提供了分子证据（Tsankova et al., 2006）。这些结果表明，对自杀行为的病因学和病理生理学的新见解可以从自杀完成者死后大脑的表观遗传修饰的进一步研究中获得。进行大规模表观遗传学研究的工具才刚刚出现，我们在约翰霍普金斯大学的表观遗传学中心一直是开发此类工具的领导者，已经创建了用于全基因组DNA甲基化（DNAm）研究的综合高通量相对甲基化阵列（CHARM）方法（Irizarry等人，2008）。我们现在建议对dna进行全基因组评估，使用CHARM和从情绪障碍自杀完成者和对照组的死后大脑的额叶皮质（BA10）样本。有希望的dna区域将使用亚硫酸盐焦磷酸测序进行验证，验证的候选基因将在自杀完成者中筛选差异表达。为了实现这一目标，我们在表观遗传学、遗传学、生物统计学和精神病理学方面组建了一支杰出的研究团队。自杀行为中差异甲基化基因和基因组区域的鉴定和表征将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；c)提供生成体内模型所需的数据，用于测试治疗靶点。这些关于自杀发病机制的新见解可能会使我们在减轻这种毁灭性表型的全球负担方面取得巨大进展。