We were initially motivated to study Per3 because chronic restraint upregulates the expression of this gene in both B6 and D2 parental strains,13 and because the expression of Per3 is associated with a highly significant cis-QTL in the BXD family. Per1 and Per2 were also upregulated by the same restraint stress protocol, but unlike Per3, expression of these two genes is not self regulated. The very strong cis-regulation of Per3 with a likelihood ratio statistic of ∼160 (LOD ∼35) in some brain regions made this gene a prime candidate for an analysis of downstream consequences of expression differences using reverse complex trait analysis.45, 56 We found that variation in expression of Per3 has downstream effects on stress response, anxiety-associated traits and addiction-related behavior (Figure 4). The Per3 downstream network also modulates 48 transcripts associated with circadian rhythm, stress response, alcoholism and schizophrenia. Of seven downstream genes that are also differentially expressed between KO and wildtype, three genes (Cast, Trpm2 and Pdlim5) are associated with stress response, alcoholism and schizophrenia. Cast was identified as the susceptibility gene for alcohol dependence through
