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Identification of risk alleles for human behavioral disorders through genomewide association studies (GWAS) has been hampered by a daunting multiple testing problem. This problem can be circumvented for some phenotypes by combining genomewide studies in model organisms with subsequent candidate gene association analyses in human populations. Here, we characterized genetic networks that underlie the response to ethanol exposure in Drosophila melanogaster by measuring ethanol knockdown time in 40 wild-derived inbred Drosophila lines. We associated phenotypic variation in ethanol responses with genomewide variation in gene expression and identified modules of correlated transcripts associated with a first and second exposure to ethanol vapors as well as the induction of tolerance. We validated the computational networks and assessed their robustness by transposon-mediated disruption of focal genes within modules in a laboratory inbred strain, followed by measurements of transcript abundance of connected genes within the module. Many genes within the modules have human orthologs, which provides a stepping stone for the identification of candidate genes associated with alcohol drinking behavior in human populations. We demonstrated the potential of this translational approach by identifying seven intronic single nucleotide polymorphisms of the Malic Enzyme 1 (ME1) gene that are associated with cocktail drinking in 1687 individuals of the Framingham Offspring cohort, implicating that variation in levels of cytoplasmic malic enzyme may contribute to variation in alcohol consumption.

Locomotion is an integral component of most animal behaviors and many human diseases and disorders are associated with locomotor deficits, but little is known about the genetic basis of natural variation in locomotor behavior. Locomotion is a complex trait, with variation attributable to the joint segregation of multiple interacting quantitative trait loci (QTL), with effects that are sensitive to the environment. We assessed variation in a component of locomotor behavior (locomotor reactivity) in a population of 98 recombinant inbred lines of Drosophila melanogaster and mapped four QTL affecting locomotor reactivity by linkage to polymorphic roo transposable element insertion sites. We used complementation tests of deficiencies to fine map these QTL to 12 chromosomal regions and complementation tests of mutations to identify 13 positional candidate genes affecting locomotor reactivity, including Dopa decarboxylase (Ddc), which catalyzes the final step in the synthesis of serotonin and dopamine. Linkage disequilibrium mapping in a population of 164 second chromosome substitution lines derived from a single natural population showed that polymorphisms at Ddc were associated with naturally occurring genetic variation in locomotor behavior. These data implicate variation in the synthesis of bioamines as a factor contributing to natural variation in locomotor reactivity.