Genetics of Alcohol Use Disorder: A Role for Induced Pluripotent Stem Cells?

Iya Prytkova, Alison Goate, Ronald P. Hart, Paul A. Slesinger

Alcohol use disorder (AUD) affects millions of people and costs nearly 250 billion dollars annually. Few effective FDA-approved treatments exist, and more are needed. AUDs have a strong heritability, but only a few genes have been identified with a large effect size on disease phenotype. Genome wide association studies (GWASs) have identified common variants with low effect sizes, most of which are in non-coding regions of the genome. Animal models frequently fail to recapitulate key molecular features of neuropsychiatric disease due to the polygenic nature of the disease, partial conservation of coding regions, and significant disparity in non-coding regions. By contrast, human induced pluripotent stem cells (hiPSC) derived from patients provide a powerful platform for evaluating genes identified by GWAS and modeling complex interactions in the human genome. hiPSCs can be differentiated into a wide variety of human cells, including neurons, glia and hepatic cells, which are compatible with numerous functional assays and genome editing techniques. In this review, we focus on current applications and future directions of patient hiPSC-derived CNS cells for modeling AUDs in addition to highlighting successful applications of hiPSCs in polygenic neuropsychiatric diseases. This article is protected by copyright. All rights reserved.