Clinical Genomics and Experimental Therapeutics

酒精使用障碍（AUD）是一种常见的复发性疾病，对个人和公共健康有重大影响。AUD的发展存在多种途径，包括可能相互作用的环境和遗传风险因素。我们的部分重点是确定其中的一些因素。 尽管过去在确定AUD的潜在遗传风险因素方面取得了有限的成功，但AUD的表观遗传学领域最近正在发展（Tawa et al，2016）。新的进展使得利用DNA甲基化进行复杂表型的表观基因组关联研究（EWAS）成为可能。存在一些AUD的EWAS，但它们受到样本量小、阵列捕获率低、组织类型、分析策略和数据解释的限制。目前，尚未鉴定出AUD的通用DNA甲基化位点。 鉴于酒精影响许多器官系统，我们使用来自独立队列的样本对AUD中的全基因组甲基化变异进行了跨组织和跨表型分析，这些样本涉及死后脑、血液和肝组织以及各种临床和成像表型，目的是鉴定疾病相关的甲基化DNA变异。结果表明，编码前蛋白转化酶枯草杆菌蛋白酶/Kexin 9（PCSK 9）的基因是数据集中与AUD相关的表观遗传变化的主要靶点（Lohoff et al，2017）。有趣的是，PCSK 9主要在肝脏中表达，在那里它被合成和分泌。它主要靶向肝细胞中的低密度脂蛋白胆固醇受体（LDL-R），并干扰血液中LDL胆固醇（LDL-C）的调节。饮酒对PCSK 9表达的表观遗传调节是解释重度饮酒患者脂质代谢异常的一种潜在机制，另一方面也解释了轻度至中度饮酒对心血管（CV）的保护作用。 我们的部门还继续根据临床方案15-AA-0127招募：（Epi）酒精依赖中恐惧消退的遗传调节剂。该方案旨在研究有和没有早期生活压力的AUD个体中恐惧消退的潜在神经生物学和神经回路。征聘工作正在进行。与该项目相关，我们完成了一项关于广泛性焦虑症患者对文拉法辛XR治疗反应的全基因组关联研究（Jung et al，2017）。我们确定了几个可能预测与治疗反应相关的提示性变异。 临床基因组学和实验治疗学部分（SCGET） 1.开展临床前研究和转化临床研究，重点关注基因组学 以及与酒精使用障碍和成瘾的病理生理学和治疗相关的表观遗传学。 2.临床前工作的重点是确定参与成瘾的分子机制， 利用广泛的方法，包括人类群体遗传学、全基因组 基因分型方法，下一代DNA和RNA测序，以及 表观遗传/蛋白质组学分析。 3.这些发现被转化为使用分子生物标志物的人类临床研究， 药物遗传学、表观遗传学和功能成像遗传学方法。 4.临床研究包括由分子生物标志物分析指导的实验性新疗法的早期1期/2期概念验证研究。

Alcohol Use Disorder (AUD) is a common relapsing disorder with significant effects on personal and public health. Various pathways to the development of AUD exist and include both environmental and genetic risk factors that likely interact with each other. Our section is focused on identifying some of those factors. Although there has been limited success in the past in identifying underlying genetic risk factors for AUD, the field of epigenetics in AUD is recently developing (Tawa et al, 2016). New advances are making it feasible to conduct epigenome-wide association studies (EWAS) of complex phenotypes using DNA methylation. A few EWAS for AUD exist, but they are limited by small sample size, low array capture, tissue type, analysis strategy and data interpretation. Currently, no universal DNA methylation loci for AUD have been identified. Given that alcohol affects many organ systems, we performed a cross-tissue and cross-phenotypic analysis of genome wide methylomic variation in AUD using samples from independent cohorts involving post-mortem brain, blood and liver tissue as well as various clinical and imaging phenotypes with the goal of identifying disease-associated methylomic DNA variation. Results show that the gene encoding the enzyme Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) was the primary target of epigenetic changes relevant to AUD across data sets (Lohoff et al, 2017) . Interestingly, PCSK9 is predominantly expressed in the liver, where it is synthesized and secrete. It primarily targets low-density lipoprotein cholesterol receptors (LDL-R) in the liver cells and interferes with the regulation of LDL cholesterol (LDL-C) in the blood. Epigenetic regulation of PCSK9 expression by alcohol consumption is one potential mechanism explaining lipid metabolism abnormalities found in patients with heavy alcohol use and on the flip-side explaining protective cardiovascular (CV) effects of light to moderate alcohol consumption. Our section also continued to recruit under the clinical protocol 15-AA-0127: (Epi)Genetic Modulators of fear extinction in Alcohol Dependence. This protocol aims to investigate underlying neurobiology and neurocircutiries of fear extinction in individuals with AUD with and without early life stress. Recruitment is ongoing. Related to this project we completed a whole genome association study of treatment response to Venlafaxine XR in generalized anxiety disorder (Jung et al, 2017). We identified several suggestive variants that might predict association with treatment response. In summary, The Section on Clinical Genomics and Experimental Therapeutics (SCGET) 1. Conducts pre-clinical studies and translational clinical studies with focus on genomics and epigenetics related to the pathophysiology and treatment of alcohol use disorders and addictions. 2. Pre-clinical work focuses on identifying molecular mechanisms involved in addictions, utilizing a wide array of methods including human population genetics, genome wide genotyping approaches, next-generation DNA and RNA sequencing, and epigenetic/proteomic profiling. 3. Findings are translated into human clinical studies using molecular biomarker, pharmacogenetic, epigenetic and functional imaging genetic approaches. 4. Clinical studies include early phase 1 / phase 2 proof-of-concept studies of experimental novel therapeutics guided by molecular biomarker profiling.