Chrna5, which encodes the α5 subunit of the nicotinic acetylcholine receptor (nAChR), is a crucial gene. nAChRs are ligand-gated ion channels, and the α5 subunit is involved in the function of these receptors. The CHRNA5-CHRNA3-CHRNB4 gene cluster, where Chrna5 is located, is associated with the regulation of neurotransmission, especially in the context of the cholinergic system, which is important for processes like attention and reward-related behaviors [3,6,7].

Genetic variation in Chrna5 has been linked to multiple diseases. In human populations, the single nucleotide polymorphism (SNP) D398N in Chrna5 has been associated with addiction to nicotine, opioids, cocaine, and alcohol [2]. A meta-analysis showed that the rs16969968 polymorphism in Chrna5 is associated with an increased risk of lung cancer in European-ancestry populations, with the minor allele A increasing the risk in both smokers and non-smokers [1]. Another meta-analysis found that the rs16969968 allele (A) is associated with a lower likelihood of smoking cessation and an earlier age of lung cancer diagnosis in European-ancestry studies [4]. In addition, Chrna5 expression is increased in human hepatocellular carcinoma (HCC) tissues, and in vitro and in vivo assays in HCC models show that Chrna5 regulates cell proliferation, stemness, metastasis, and sorafenib sensitivity by regulating YAP activity and relevant genes [5]. In psoriasis, Chrna5 is highly expressed in psoriatic lesional skin, and Chrna5-knockout mice show reduced psoriasis severity, indicating its role in psoriasis development through the MAPK kinase kinase-1/c-Jun N-terminal kinase‒MAPK/NF-κB pathway [8]. In head and neck squamous cell carcinoma (HNSC), nicotine promotes cell proliferation, migration, and invasion by upregulating Chrna5 expression, and knockdown of Chrna5 reduces these effects [9].

In conclusion, Chrna5 is important in the function of nicotinic acetylcholine receptors and is associated with various diseases, including addiction, lung cancer, HCC, psoriasis, and HNSC. The use of genetic models such as knockout mice has helped to reveal its role in disease-related biological processes, providing insights into potential therapeutic targets for these diseases.