Figure 6.
Many of the top DE genes are located near genetic variants that segregate bHR/bLR rats within QTLs for exploratory locomotor activity. (A) Our concurrent genetic study used exome sequencing to identify SNVs that segregated bHR/bLR rats in our colony (25). A high percentage of bHR/bLR DE genes (adult meta-analysis: FDR ˂ .05) were found within ±100, 250, or 500 kb or 1 MB of these segregating variants, using either traditional (Bonferroni-corrected p ˂ .05) or more stringent (Bonferroni-corrected p ˂ 5.00 × 10−5) criteria to define segregation. An asterisk (*) designates enrichment (Fisher’s exact test: p ˂ .0001) in comparison with the non-DE genes in our meta-analysis (FDR > .05). (B) Our concurrent genetic study used a sampling of bHR/bLR segregating variants to identify QTLs for exploratory locomotor activity in a novel field using a bHRxbLR F2 intercross (25). bHR/bLR DE genes (adult meta-analysis: FDR ˂ .05) were 4.5 times more likely to overlap (±1 MB) QTLs for exploratory locomotion than other genes included in our meta-analysis (Fisher’s exact test: p = .0035). (C) A table illustrating the top genes from our meta-analyses (FDR ˂ .10; bold + italic = FDR ˂ .05) that overlap (±1 MB) significant (LOD > 4) and putative (LOD > 3) QTLs for exploratory locomotion identified by our concurrent genetic study (25). Also depicted is overlap with QTLs identified in the Rat Genome Database (41) for the following behaviors relevant to the bHR/bLR phenotype: anxiety (56–61), stress-related responses (62–64), and behavioral despair (65). (D) The top chromosomal loci enriched for bHR/bLR DE genes overlap previously identified QTLs relevant to externalizing and internalizing behaviors. The top chromosomal loci enriched for bHR/bLR DE genes were identified using PGE analysis: location (full coordinates, defined to include the start coordinates for all genes with p ˂ .01 in the P14 or adult meta-analysis in the region), p value, FDR, and enrichment score. Also depicted is the overlap (±1 MB) of these enriched chromosomal loci with QTLs for exploratory locomotor activity (25) as well as with QTLs identified in the Rat Genome Database (41) for anxiety (56–59), stress-related responses (62–64,73–75), and behavioral despair (65). Enrichment Score: ratio of genes with p ˂ .01 out of all genes in the region. bHR, bred high-responder; bIR, bred intermediate-responder; bLR, bred low-responder; Chr, chromosome; DE, differentially expressed; FDR, false discovery rate; LOD, logarithm of the odds score; MB, megabase; PGE, positional gene enrichment; P-value, nominal p value; QTLs, quantitative trait loci; SNV, single nucleotide variant.