Association of metabotropic glutamate receptor 7 gene with nicotine dependence in a Chinese Han population: A cross-sectional candidate-gene association study.

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 whole-gene 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.