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Chunk #26 — Discussion

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GABRA2 Alcohol Dependence Risk Allele is Associated with Reduced Expression of Chromosome 4p12 GABAA Subunit Genes in Human Neural Cultures.
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We found that relative levels of RNA for the chr4p12 GABAA subunit genes GABRG1, GABRA2, GABRA4, and GABRB1 were significantly inter-correlated in neural cultures derived from iPSC lines. RNA levels for these GABAA subunits identified distinct low-expression and high-expression clusters of cell lines. The low-expression cluster had a higher frequency (0.76 vs. 0.34) of AD-associated GABRA2 rs279858*C alleles than the high-expression cluster. Examination of next-generation RNA–Seq data available for 10 neural cell lines allowed us to extend our analysis to include the expression of GABAA genes located on multiple chromosomes. RNA-Seq data confirmed our qPCR results showing low expression of chr4p12 GABAA genes in cell lines that comprise Cluster 1, and extended our findings by showing that GABAA subunit genes located on other chromosomes showed no difference in expression as a function of expression cluster. Furthermore, transcripts of the GNPDA2 (glucosamine-6-phosphate deaminase 2) and COMMD8 (COMM domain-containing protein 8) genes that flank the chromosome 4 GABAA cluster were readily detected in samples in which the four GABAA genes were minimally expressed. Together, these RNA-Seq and qPCR results suggest that the