Genomewide search for epistasis in a complex trait: Pentobarbital withdrawal convulsions in mice

The well-documented difference in pentobarbital withdrawal severity between DBA/2J and C57BL/6J mice offers the opportunity to study how differences b etween allelic variants influence pentobarbital withdrawal via their additi ve and/or dominance effects and to identify modifier loci that also influen ce the trait via gene-gene interactions (a form of epistasis). Previous wor k in our laboratory identified seven provisional quantitative trait loci (Q TLs) for pentobarbital withdrawal using BXD recombinant inbred strains. To date, only one of these QTLs has been confirmed, Pbwl. We hypothesized that other loci that act epistatically may also influence genetic variance in p entobarbital withdrawal severity. Using Epistat, a program developed to car ry out full-genome searches for epistasis, we identified six provisional ep istatic interactions (P < .002) between the provisional QTLs and modifier l oci elsewhere in the genome. Verification testing of these interactions usi ng 404 B6D2F(2) mice provided supporting evidence that a QTL on chromosome 11 contributes to genetic variance in pentobarbital withdrawal, but only in the presence of a modifier allele on distal chromosome 1 (P = .0004). This modifier is in the same genomic vicinity as loci detected for a variety of withdrawal and seizure phenotypes.