Sunday, November 24, 2024
11/24/2024
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.
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