| Autor: |
Goetjen, Alexandra, Watson, Maegan, Lieberman, Richard, Clinton, Kaitlin, Kranzler, Henry R., Covault, Jonathan |
| Zdroj: |
American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics: The Official Publication of the International Society of Psychiatric Genetics; December 2020, Vol. 183 Issue: 8 p464-474, 11p |
| Abstrakt: |
Twin studies indicate that there is a significant genetic contribution to the risk of developing alcohol use disorder (AUD). With the exception of coding variants in ADH1Band ALDH2, little is known about the molecular effects of AUD‐associated loci. We previously reported that the AUD‐associated synonymous polymorphism rs279858 within the GABAAα2 receptor subunit gene, GABRA2, was associated with gene expression of the chr4p12 GABAAsubunit gene cluster in induced pluripotent stem cell (iPSC)‐derived neural cultures. Based on this and other studies that showed changes in GABRA2DNA methylation associated with schizophrenia and aging, we examined methylation in GABRA2. Specifically, using 69 iPSC lines and neural cultures derived from 47 of them, we examined whether GABRA2rs279858 genotype predicted methylation levels and whether methylation was related to GABAAreceptor subunit gene expression. We found that the GABRA2CpG island undergoes random stochastic methylation during reprogramming and that methylation is associated with decreased GABRA2gene expression, an effect that extends to the GABRB1gene over 600 kb distal to GABRA2. Further, we identified additive effects of GABRA2CpG methylation and GABRA2rs279858 genotype on expression of the GABRB1subunit gene in iPSC‐derived neural cultures. |
| Databáze: |
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