Prioritization Of Genes Related To Nicotine Addiction

Objective: Nicotine has a broad impact on the central as well as the peripheral nervous system. Long-term exposure to nicotine will result in the dependence on it, i.e. nicotine addiction. In the past decades, lots of genes related to nicotine addiction have been uncovered by many studies via various studies. But the exact mechanisms under it are still largely unknown. It is important to screen the genes that are worthy of further research in nicotine addiction via gene prioritization methods.Methods: Here, we proposed a multi-source-based method for gene prioritization and used it in nicotine addiction. First, the previous studies about nicotine addiction from four fields, i.e., genetic association analysis, genetic linkage analysis, high-throughput gene/protein expression analysis and literature search of single gene/protein-based studies, were collected. Then, the four fields were assigned different weights according to the information they contained. The genes were scored according to the weights of the four fields and the fields they involved in. Finally, the casual genes of nicotine addiction were selected out based on the thresholds we set. Topp Gene was used for the functional enrichment analysis of the casual genes. The enriched pathways of the casual genes were got through Ingenuity Pathway Analysis. Besides, we developed a functional-similarity-based method to screen out the casual genes of nicotine addiction. In this method, we first obtained the genes that annotated by the three categories of Gene Ontology(GO), i.e. Biological Process(BP) ontology terms, Molecular Function(MF) ontology terms and Cellular Component(CC) ontology terms, from the human genome. Then, a set of genes that have been identified as casual genes of nicotine addiction via experiments(known genes) and their corresponding GO terms were obtained and used as test set. The threshold that used to screen the casual genes was obtained by Monte Carlo method to get the casual genes. Finally, the Database for Annotation, Visualization and Integrated Discovery was used for the pathway analysis of the casual genes.Results:In the multi-source-based method, the weight of genetic association analysis, genetic linkage analysis, high-throughput gene/protein expression analysis and literature search of single gene/protein-based studies was 0.403, 0.129, 0.203 and 0.265 respectively. 220 and 580 casual genes of nicotine addiction were screened out respectively according to the thresholds of 0.665 and 0.598. Biological processes that related to Cell-cell signaling, Synaptic transmission, Response to oxygen-containing compound, Transmission of nerve impulse and etc were found enriched in the top 220 casual genes. Also, the casual genes were significantly enriched in the pathways of c AMP-mediated signaling, Calcium signaling, G-Protein coupled receptor signaling, Dopamine receptor signaling, GABA receptor signaling and etc. Those biological processes and pathways have been proved to be associated with nicotine addiction or alcohol addiction by many studies. It suggested the reliable of our study and the casual genes were promising targets for further research in nicotine addiction. In the functional-similarity-based method, we firstly obtained 37545 genes from NCBI Gene database; then, 17435 out of those genes were annotated by at least BP ontology terms or MF ontology terms; finally, 200 casual genes were obtained. The pathway analysis indicated that those genes were mainly enriched in the pathways that related to addiction or other nervous system diseases.Conclusions: We presented a multi-source-based and a functional-similarity-based method for gene prioritization of nicotine addiction. Through the two methods, we obtained two lists of casual genes of nicotine addiction. The aspects of information that the two methods used make the two methods complement each other and the combination of the two methods would be helpful in the identification of casual genes and the interpretation of the mechanism of nicotine addiction. Besides, the functional enrichment analysis and pathway analysis of the two lists of casual genes indicated that they were mainly involved in nicotine or alcohol addiction and other nervous system diseases. This indicated the reproducibility of our study. Besides nicotine addiction, it was suitable for gene prioritization of other nervous system disorders.