Clinical Genomics and Experimental Therapeutics

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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.