A second unexpected observation was the discordance in cluster assignment for pairs of neural cell lines derived from 4 individual donors. The 36 iPSC lines examined included 2 independent iPSC clones from each of 15 donor subjects. Paired lines from 11 donors (9 rs279858 homozygotes and 2 heterozygotes) were concordant (i.e., both lines from a given donor were grouped in the same Cluster), while paired lines from 4 subjects (1 rs279858*T/T, 1 C/C, and 2 T/C) were discordant. We speculate that the AD-associated rs279858*C-allele is in moderate but not complete linkage disequilibrium with an as-yet-unidentified repressive functional variant, and that iPSC-derived rs279858 homozygote neural cells that are discordant in chr4p12 GABAA gene expression are in fact heterozygous for this unidentified functional variant. Allelic bias could then reveal the cis-effect of the functional repressive C-allele linked variant in heterozygotes. Our results demonstrating a modest allelic bias in expression of the entire chr4p12 GABAA gene region (e.g. Figure 6) suggests that allelic bias may partially explain the complex genetic regulatory features in this region.
