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5. Collaborative Study on the Genetics of Alcoholism: Functional genomics |
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| Authors: | Isabel Gameiro-Ros Dina Popova Iya Prytkova Zhiping P. Pang Yunlong Liu Danielle Dick Kathleen K. Bucholz Arpana Agrawal Bernice Porjesz Alison M. Goate Xiaoling Xuei Chella Kamarajan COGA Collaborators Jay A. Tischfield Howard J. Edenberg Paul A. Slesinger Ronald P. Hart |
| Affiliation: | 1. Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA;2. Human Genetics Institute of New Jersey, Rutgers University, Piscataway, New Jersey, USA;3. Human Genetics Institute of New Jersey, Rutgers University, Piscataway, New Jersey, USA Child Health Institute of New Jersey and Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey, USA;4. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA;5. Rutgers Addiction Research Center, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey, USA;6. Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA;7. Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, New York, USA;8. Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA;9. Human Genetics Institute of New Jersey, Rutgers University, Piscataway, New Jersey, USA Department of Genetics, Rutgers University, Piscataway, New Jersey, USA;10. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA Department of Medical and Molecular Genetics, Indiana University, Indianapolis, Indiana, USA |
| Abstract: | Alcohol Use Disorder is a complex genetic disorder, involving genetic, neural, and environmental factors, and their interactions. The Collaborative Study on the Genetics of Alcoholism (COGA) has been investigating these factors and identified putative alcohol use disorder risk genes through genome-wide association studies. In this review, we describe advances made by COGA in elucidating the functional changes induced by alcohol use disorder risk genes using multimodal approaches with human cell lines and brain tissue. These studies involve investigating gene regulation in lymphoblastoid cells from COGA participants and in post-mortem brain tissues. High throughput reporter assays are being used to identify single nucleotide polymorphisms in which alternate alleles differ in driving gene expression. Specific single nucleotide polymorphisms (both coding or noncoding) have been modeled using induced pluripotent stem cells derived from COGA participants to evaluate the effects of genetic variants on transcriptomics, neuronal excitability, synaptic physiology, and the response to ethanol in human neurons from individuals with and without alcohol use disorder. We provide a perspective on future studies, such as using polygenic risk scores and populations of induced pluripotent stem cell-derived neurons to identify signaling pathways related with responses to alcohol. Starting with genes or loci associated with alcohol use disorder, COGA has demonstrated that integration of multimodal data within COGA participants and functional studies can reveal mechanisms linking genomic variants with alcohol use disorder, and potential targets for future treatments. |
| Keywords: | alcohol use disorder (AUD) brain gene expression genomics induced pluripotent stem cells neuronal function |