Table 1.
GABA(A)R expression summary.
Figure 1.
Summary of significant genetic regulation in the hippocampus.
Probe sets represent columns and ascending genomic location for each chromosome represent rows. Only chromosomes with a significant QTL (LRS>15) are shown. Several GABA(A)R subunits are regulated by both cis and trans eQTL (Gabra1, Gabra2, Gabrb2, and Gabrb3) whereas some are modified exclusively in trans (Gabra5, Gabrg1). Hue intensity provides an indication of the strength of the association between gene expression and genomic location. Red and blue alleles indicate that the D or B allele increases trait values, respectively. Arrowheads show the location of each cognate gene. PC1 = first principal component, Chr = Chromosome, Mb = Megabase, Prox = proximal, mid = middle, dist = distal.
Figure 2.
Consistency of cis modulation across tissues.
Genetic regulation of the 5 subunits regulated by strong cis eQTLs in the hippocampus was compared across three different platforms Affymetrix M430 (WB = whole brain, CB = cerebellum), Affymetrix MoGene 1.0 ST (AMY = amgydala and HYP = hypothalamus), and Illumina (CTX = neocortex, STR = striatum). Each probe set was required to have a mean expression of at least 8 in each tissue database. Blue and red indicate an association between the B6 and D2 allele at each locus and higher probe set expression, respectively. The more intense hue indicates a greater association and a corresponding increase in significance. For all data except the HYP and AMY, probes overlapping SNPs were filtered out and a principal component analysis was performed on remaining probes to capture a component (PC1) explaining the majority of the variation in probe set expression. Percent of variance explained by each PC1 ranged from (∼45% to 95%). Because of the large number of probes included for measurement in the HYP and AMY, a probe level analysis was not possible. Some probe sets (indicated by *) contained 1 to 3 probes overlapping a variant. It is hard to predict the overall effect of these variants but, in general, those probe sets with SNPs that have higher expression associated with the B6 allele (blue) have a higher chance of being false due to SNP artifacts. Cis modulation of expression across tissues is most consistent for Gabra2 and Gabra1.
Figure 3.
Summary of genetic regulation of GABA(A) R subunits across transcript features.
Genetic regulation of exon, intron, and 3′ UTR features for each of the five subunits regulated by strong cis eQTLs was measured in the hippocampus using the Affymetrix exon platform (database accession number GN206). Each probe set was required to have a mean expression of at least 10 and all probe sets overlapping SNPs were excluded. Blue and red indicate an association between the B6 and D2 allele at each locus and higher probe set expression, respectively. The more intense hue indicates a greater association and a corresponding increase in significance. Only Gabra2 shows strong consistency of genetic regulation across mRNA regions.
Table 2.
Summary of GABA(A)R subunit cis modulation among several genetic crosses.
Figure 4.
Coexpression of GABA(A) Receptor subunits in the hippocampus.
Bold lines indicate a correlation between 1 and 0.7 while normal and dashed lines indicate a correlation between 0.7 and 0.5 and 0.5 and 0.3, respectively. Warm colors represent positive correlations while cool colors represent negative correlations. Probes containing SNPs were removed and a principal component analysis (PCA) was used on the remaining probes to capture the component explaining the majority of the expression variation (PC1) in probe expression among BXD strains. PCA was used to extract PC1 for a single subunit when more than two probe sets were strongly correlated (r>0.8) and the average (AVG) was used when two probe sets were strongly correlated. prox = proximal, mid = middle. The highest positive correlations are between subunits targeting the same mRNA region. This is especially true for members of the most common heterotrimeric receptor—Gabra1, Gabrb2, and Gabrg2.
Figure 5.
Conserved members of the GABA(A)R gene network.
(A) Gabra1, Gabrb2, and Gabrg3 are generally well coexpressed across species and platforms. The set of highly conserved correlates include many synaptic genes such as Syt1 and Sh3gl2. Bold lines indicate a correlation between 1 and 0.7 while normal and dashed lines indicate a correlation between 0.7 and 0.5 and 0.5 and 0.3, respectively. Warm colors represent positive correlations while cool colors represent negative correlations. (B) Expression of conserved module members is regulated by Trans5a. LRS score and additive effect are shown on the Y axis in blue and green, respectively. The blue line plots the strength of the association between gene expression and chromosomal location. The genome wide significant and suggestive threshold is shown by the red and grey horizontal line, respectively. Red and green lines show the effect of the D or B allele on trait values, respectively. The upper X-axis shows location by chromosome and the lower X-axis shows location in megabases.