Identification and molecular functional analysis of genes associated with addiction using integrated genetic...

Addiction is a chronic, relapsing neuropsychiatric disorder despite adverse consequences. Addiction involves neurobiological changes in the reward, motivation, and memory systems, particularly affecting the dopaminergic pathways due to a complex interaction between inherited traits and life experiences.

To explore the role of genes in addictive behavior, we compiled a list of 332 clinically relevant genes from literature sources and searched GeneAnalytics, STRING web-based programs, and integrated genetic and protein databases for interactions and molecular profiles of genes in tissues and cells, diseases, pathways, biological processes, cellular components, functions, phenotypes, and compounds.

We identified 332 genes associated with addictive behavior and predominantly expressed in the brain associated with schizophrenia, nervous system disorders, and cancer. Nine of the top 10 related pathways showed GPCR protein interaction and signaling involving the CREB1, MAPK1, MAPK3, and AKT1 genes. The BDNF gene was recognized in eight of the top 10 high-scoring phenotypes involving the neurotransmitters dopamine and glutamate. We chose to study AKT1 as the most identified gene when searching web-based programs and integrated genetic and protein databases. This gene encodes protein kinases that are required for protein phosphorylation, fundamental for most cellular functions, stabilization, regulation of targeted proteins including cell cycle control and signal transduction, neuron formation, and neurological function including the hippocampus. We identified the important PI3/AKT/mTOR signaling pathway that integrates extracellular growth signals, promotes proliferation, and inhibits apoptosis, which is important for brain function. These genes also overlap with other genes associated with ATPase activity, metabolism, and chaperone protein functions that play a role in addiction. In addition, we identified 29 genes that are shared with alcoholism/alcohol use disorder and overlap with interactive molecular functions and processes between alcoholism and addiction.

Our study identified 332 addiction genes from literature sources and used in silico integrated genetic approaches with two searchable web-based programs to provide insights into the complex molecular and genetic architecture of addiction. We identified cell cycle control factors, extracellular growth, signal transduction, and metabolism. The pathways involved selective protein phosphorylation and transduction of proteins as well as neurotrophic factors with mechanisms impacting nervous system development, plasticity and function when disturbed, leading to addictive behavior. Several genes associated with addiction overlapped with those associated with alcohol use disorder.