Identification of Pathogenic Missense Mutations in the CHRNA5 Gene: A Computational Approach

Abstract

Aim The CHRNA5/A3/B4 gene locus is closely related to nicotine dependence and other smoking-related disorders. Coupling genetic and clinical studies of nicotine dependence and smoking behaviors may open new avenues for medication development. The aim of this study is to investigate the functional missense mutations in the CHRNA5 gene. Methodology The Ensembl database was used to gather data on missense mutations of the human CHRNA5 gene. Computational tools viz. SIFT (Sorting Intolerant From Tolerant), PolyPhen (Polymorphism Phenotyping), PROVEAN (Protein Variation Effect Analyzer), I-Mutant, and MutPred were used to uncover the pathogenic mutations in the gene under investigation. Results Among 161 missense variants reported inthe CHRNA5 gene, 94 variants were found to be highly pathogenic. Moreover, 20 were pathogenic and 4 were not pathogenic. Conclusion The computational analysis disclosed harmful mutations in the CHRNA5 gene which could be potentially associated with smoking-related traits.

Keywords: chrna5; genetics; genome-wide association study; nicotine dependence; smoking.

Figure 1. Schematic representation of the present investigation on the missense variants of CHRNA5 gene

Figure 2. Percentage distribution of damaging and not damaging mutations as assessed by PROVEAN, SIFT, PolyPhen

PROVEAN: Protein Variation Effect Analyzer, SIFT: Sorting Intolerant From Tolerant, PolyPhen: Polymorphism Phenotyping

Figure 3. Percentage distribution of mutations with increased and decreased stability as assessed by I-Mutant

Figure 4. Percentage distribution of highly pathogenic, pathogenic, and not pathogenic mutations as assessed by MutPred