Functional Validation of Alcohol Dependence-Associated FYN Variants Using Gene Editing and Stem Cell Study Approaches.

Alcohol dependence (AD) is one of the most prevalent neuropsychiatric disorders. Multiple polymorphisms in the Fyn tyrosine kinase gene (FYN) were found to be associated with AD. The function of AD-associated FYN variants remains largely unknown due to the absence of an appropriate model for studying them. Here, we generated human embryonic stem cell lines homozygous/heterozygous for rs706895 C/T alleles in 5' untranslated region (5' UTR) of FYN by CRISPR-Cas9 editing to explore the AD association. Transcriptome and reporter gene analyses demonstrated that induced neurons with the rs706895 C allele showed a significantly higher expression level of FYN under ethanol treatment. Our results suggest that FYN 5' UTR variant rs706895 may influence an individual's vulnerability to AD by altering FYN expression. Targeting AD-associated variants may provide a better understanding of disease mechanisms and a reliable basis for the personalized AD treatment.