Jinjie Zhao, Mengying Li, Ruibo Wang, Wenjing Shen, Meng Li
INTRODUCTION Despite a global decline in prevalence, cigarette smoking remains a significant public health issue.Tobacco addiction is principally caused by nicotine dependence (ND).This study aimed to investigate the relationship between the metabotropic glutamate receptor 7 (GRM7) gene and ND in Chinese adults.METHODS This two-stage, cross-sectional, candidate-gene association study first enrolled a discovery cohort of 1609 participants from Kunming, Yunnan, China (2017-2019), followed by a replication stage involving 1329 individuals from Jincheng and Taiyuan, Shanxi, China (2012-2013).Association analysis between the GRM7 gene and ND was performed at individual SNP, haplotype, and wholegene levels.Logistic and linear regression models were employed for single-SNP association analyses.Heaviness of smoking index (HSI) and Fagerström test for nicotine dependence (FTND) were used to assess ND.RESULTS Rs77452956, rs74791991, and rs2176404 were significantly associated with ND proxied by HSI, with p-values of <0.001, 0.001, and 0.002, respectively.In the replication analysis, rs74791991 and rs2176404 showed associations with ND (p=0.006 and 0.082, respectively), while rs77452956 was linked to smoking status (p=0.014).Haplotype-based association analysis revealed that two haplotypes, C-C-T and T-G-C, comprising rs74791991, rs111848366, and rs7633313, were associated significantly with HSI, with p<0.001 and p=0.003, respectively.Gene-based analysis also revealed a significant association between GRM7 and HSI (p=0.006).Functional assessment suggested that rs77452956 and rs74791991 have regulatory capacity.Furthermore, the derived C alleles of rs74791991, rs2176404, and rs77452956 showed accelerated evolution.CONCLUSIONS We identified three SNPs, rs74791991, rs2176404, and rs77452956, associated with ND in Han Chinese individuals.Our findings suggest a potential role of GRM7 in susceptibility to smoking-related behaviors and warrant further investigation to determine its relevance in smoking cessation.