Gene‐based association analysis reveals involvement of LAMA5 and cell adhesion pathways in nicotine dependence in African‐ and European‐American samples

Abstract

Nicotine dependence (ND) is a chronic brain disorder that causes heavy social and economic burdens. Although many susceptibility genetic loci have been reported, they can explain only approximately 5%–10% of the genetic variance for the disease. To further explore the genetic etiology of ND, we genotyped 242 764 SNPs using an exome chip from both European‐American (N = 1572) and African‐American (N = 3371) samples. Gene‐based association analysis revealed 29 genes associated significantly with ND. Of the genes in the AA sample, six (i.e., PKD1L2, LAMA5, MUC16, MROH5, ATP8B1, and FREM1) were replicated in the EA sample with p values ranging from 0.0031 to 0.0346. Subsequently, gene enrichment analysis revealed that cell adhesion‐related pathways were significantly associated with ND in both the AA and EA samples. Considering that LAMA5 is the most significant gene in cell adhesion‐related pathways, we did in vitro functional analysis of this gene, which showed that nicotine significantly suppressed its mRNA expression in HEK293T cells (p < 0.001). Further, our cell migration experiment showed that the migration rate was significantly different in wild‐type and LAMA5‐knockout (LAMA5‐KO)‐HEK293T cells. Importantly, nicotine‐induced cell migration was abolished in LAMA5‐KO cells. Taken together, these findings indicate that LAMA5, as well as cell adhesion‐related pathways, play an important role in the etiology of smoking addiction, which warrants further investigation.

Identification of a Novel Functional Non-synonymous Single Nucleotide Polymorphism in Frizzled Class Receptor 6 Gene for Involvement in Depressive Symptoms

“…First-strand cDNAs were synthesized from 1 μg of total RNA using an iScript cDNA Synthesis Kit (Bio-Rad, Hercules, CA, United States). The qRT-PCR amplification was conducted in a volume of 10 μl containing 5 μl of 2 × Power SYBR Green PCR Master Mix (Applied Biosystems), mixed with equal amounts of sense and antisense primers (2.5 μl; final concentration 250 nM each), and 2.5 μl of diluted cDNA in a 384-well plate using 7900 HT Fast Real Time PCR system (Applied Biosystems) as described previously ( Yang et al, 2016 ; Han et al, 2019 ; Chen et al, 2020 ; Fan et al, 2021 ). The PCR conditions were as follows: 50°C for 2 min, 95°C for 10 min, followed by 40 cycles of 95°C for 15 s and 60°C for 1 min.…”

Synergistic effects of early psychosocial factors and polygenic risk for smoking: a cross sectional analysis of a sample of older adults in the US

“…Cigarette smoking is a complex behavior determined by an interaction of environmental, developmental, and genetic effects, and it is currently the leading cause of preventable death worldwide [1]. Twin studies suggest that smoking initiation and persistence is 40-60% heritable [2], and genome-wide association studies (GWAS) reveal genetic variants associated with smoking behaviors (e.g., nicotine dependence, smoking initiation) [3,4]. The genetic variants identi ed are aggregated into a single index of genetic risk for the phenotype and called polygenic scores (PGSs).…”