Genetics of Cocaine Sensitivity in Drosophila

SUMMARY
Illegal use of cocaine and other drugs is a worldwide health problem. The National Institute on Drug Abuse
estimates the total costs of drug abuse and addiction due to use of tobacco, alcohol and illegal drugs at $820
billion a year, making substance abuse the most costly public health problem in the nation. Illicit drug use alone
accounts for $193 billion in health care, productivity loss, crime, incarceration, and drug enforcement. In
humans, susceptibility to the effects of cocaine and other drugs has a strong genetic component, but little
progress has been made in identifying the underlying variants and genes, in part due to difficulty in obtaining
sufficiently large sample sizes because of criminalization of substance abuse; variation in drug exposure,
including simultaneous exposure to multiple drugs, alcohol and nicotine; and comorbidity with other
neuropsychiatric disorders. These problems can be mitigated using model organisms, such as Drosophila
melanogaster. In addition to benefits of low rearing costs, small size and a short generation interval, Drosophila
has a wealth of publically available genetic resources. Importantly, many effects of psychostimulants on people
are replicated in flies. Approximately 67% of fly genes have human orthologs, and therefore insights gained
from Drosophila have translational potential. During the past period of support, we have used the D.
melanogaster Genetic Reference Panel of inbred wild-derived fly strains with fully sequenced genomes, and
outbred advanced intercross populations (AIPs) derived from DGRP lines, to perform genome wide association
(GWA) analyses of drug consumption behaviors and gene expression. These analyses showed that variants
associated with drug consumption phenotypes were largely located in non-coding genomic regions, and
presumably exert their phenotypic effects via modulation of gene regulation. We derived gene regulatory
networks from naturally occurring genetic variation in gene expression and constructed an atlas of gene
expression changes in the Drosophila brain following cocaine exposure at single cell resolution. The challenge
now is to understand how variants act jointly to affect variation in drug preference, and to determine the
underlying molecular networks using systems genetics analyses. Here, we propose to use 1200 new DGRP
lines to map naturally occurring variants and genes associated with cocaine preference with greatly increased
power and precision than our previous studies, perform a systems genetic analysis to infer causal regulatory
networks associated with cocaine preference, and use germline gene editing to prove causality of the genetic
associations with cocaine preference and gene regulatory networks. Information obtained from these studies
can serve as a blueprint for subsequent translational studies in mammalian systems and human populations
based on orthology and evolutionary conservation of fundamental biological processes, and expand the
genetic framework associated with variation in human drug susceptibility beyond the narrow range of candidate
genes examined to date.