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
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5. Collaborative Study on the Genetics of Alcoholism: Functional genomics
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.
期刊介绍:
Genes, Brain and Behavior was launched in 2002 with the aim of publishing top quality research in behavioral and neural genetics in their broadest sense. The emphasis is on the analysis of the behavioral and neural phenotypes under consideration, the unifying theme being the genetic approach as a tool to increase our understanding of these phenotypes.
Genes Brain and Behavior is pleased to offer the following features:
8 issues per year
online submissions with first editorial decisions within 3-4 weeks and fast publication at Wiley-Blackwells
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A large and varied editorial board comprising of international specialists.