Nevada Institute of Personalized Medicine, University of Nevada Las Vegas, Las Vegas, NV.
Department of Public Health, University of Helsinki, Helsinki, FI, Finland.
Nicotine Tob Res. 2020 May 26;22(6):900-909. doi: 10.1093/ntr/ntz099.
FTND (Fagerstrӧm test for nicotine dependence) and TTFC (time to smoke first cigarette in the morning) are common measures of nicotine dependence (ND). However, genome-wide meta-analysis for these phenotypes has not been reported.
Genome-wide meta-analyses for FTND (N = 19,431) and TTFC (N = 18,567) phenotypes were conducted for adult smokers of European ancestry from 14 independent cohorts.
We found that SORBS2 on 4q35 (p = 4.05 × 10-8), BG182718 on 11q22 (p = 1.02 × 10-8), and AA333164 on 14q21 (p = 4.11 × 10-9) were associated with TTFC phenotype. We attempted replication of leading candidates with independent samples (FTND, N = 7010 and TTFC, N = 10 061), however, due to limited power of the replication samples, the replication of these new loci did not reach significance. In gene-based analyses, COPB2 was found associated with FTND phenotype, and TFCP2L1, RELN, and INO80C were associated with TTFC phenotype. In pathway and network analyses, we found that the interconnected interactions among the endocytosis, regulation of actin cytoskeleton, axon guidance, MAPK signaling, and chemokine signaling pathways were involved in ND.
Our analyses identified several promising candidates for both FTND and TTFC phenotypes, and further verification of these candidates was necessary. Candidates supported by both FTND and TTFC (CHRNA4, THSD7B, RBFOX1, and ZNF804A) were associated with addiction to alcohol, cocaine, and heroin, and were associated with autism and schizophrenia. We also identified novel pathways involved in cigarette smoking. The pathway interactions highlighted the importance of receptor recycling and internalization in ND.
Understanding the genetic architecture of cigarette smoking and ND is critical to develop effective prevention and treatment. Our study identified novel candidates and biological pathways involved in FTND and TTFC phenotypes, and this will facilitate further investigation of these candidates and pathways.
FTND（Fagerstrӧm 尼古丁依赖测试）和 TTFC（早晨第一支烟的吸烟时间）是尼古丁依赖（ND）的常见测量方法。然而，针对这些表型的全基因组荟萃分析尚未报道。
对来自 14 个独立队列的欧洲血统成年吸烟者的 FTND（N=19431）和 TTFC（N=18567）表型进行了全基因组荟萃分析。
我们发现，4q35 上的 SORBS2（p=4.05×10-8）、11q22 上的 BG182718（p=1.02×10-8）和 14q21 上的 AA333164（p=4.11×10-9）与 TTFC 表型相关。我们尝试用独立样本（FTND，N=7010 和 TTFC，N=10061）对主要候选基因进行复制，然而，由于复制样本的能力有限，这些新基因座的复制没有达到显著性。在基因分析中，COPB2 与 FTND 表型相关，而 TFCP2L1、RELN 和 INO80C 与 TTFC 表型相关。在途径和网络分析中，我们发现内吞作用、肌动蛋白细胞骨架调节、轴突导向、MAPK 信号和趋化因子信号途径之间的相互作用参与了 ND。
我们的分析确定了 FTND 和 TTFC 表型的几个有前途的候选基因，需要进一步验证这些候选基因。FTND 和 TTFC 都支持的候选基因（CHRNA4、THSD7B、RBFOX1 和 ZNF804A）与酒精、可卡因和海洛因成瘾有关，与自闭症和精神分裂症有关。我们还确定了与吸烟有关的新途径。途径相互作用突出了受体再循环和内化在 ND 中的重要性。
了解吸烟和 ND 的遗传结构对于制定有效的预防和治疗方法至关重要。我们的研究确定了与 FTND 和 TTFC 表型相关的新候选基因和生物途径，这将有助于进一步研究这些候选基因和途径。
