Associations of Prenatal Nicotine Exposure and the Dopamine Related Genes ANKK1 and DRD2 to Verbal Language

Language impairment (LI) and reading disability (RD) are common pediatric neurobehavioral disorders that frequently co-occur, suggesting they share etiological determinants. Recently, our group identified prenatal nicotine exposure as a factor for RD and poor reading performance. Using smoking questionnaire and language data from the Avon Longitudinal Study of Parents and Children, we first determined if this risk could be expanded to other communication disorders by evaluating whether prenatal nicotine exposure increases risk for LI and poor performance on language tasks. Prenatal nicotine exposure increased LI risk (OR = 1.60; p = 0.0305) in a dose-response fashion with low (OR = 1.25; p = 0.1202) and high (OR = 3.84; p = 0.0002) exposures. Next, hypothesizing that the effects of prenatal nicotine may also implicate genes that function in nicotine related pathways, we determined whether known nicotine dependence (ND) genes associate with performance on language tasks. We assessed the association of 33 variants previously implicated in ND with LI and language abilities, finding association between ANKK1/DRD2 and performance on language tasks (p≤0.0003). The associations of markers within ANKK1 were replicated in a separate LI case-control cohort (pANKK1/DRD2 contributes to language performance. More precisely, these findings suggest that prenatal environmental factors influence in utero development of neural circuits vital to language. Our association of ANKK1/DRD2 further implicates the role of nicotine-related pathways and dopamine signaling in language processing, particularly in comprehension and phonological memory.

语言损伤（Language Impairment, LI）与阅读障碍（Reading Disability, RD）均为常见的儿童神经行为障碍，且二者常共病发生，提示共享病因学决定因素。近期，本团队发现产前尼古丁暴露是阅读障碍及阅读表现不佳的危险因素。本研究借助雅芳父母与儿童纵向研究（Avon Longitudinal Study of Parents and Children）中的吸烟问卷与语言数据，首先通过评估产前尼古丁暴露是否会提升语言损伤风险及语言任务表现不佳的概率，探究该危险因素是否可推广至其他沟通障碍。产前尼古丁暴露会提升语言损伤风险（比值比[Odds Ratio, OR]=1.60；p=0.0305），且呈现剂量反应关系：低暴露组OR=1.25，p=0.1202；高暴露组OR=3.84，p=0.0002。随后，基于产前尼古丁暴露的效应可能涉及尼古丁相关通路功能基因这一假设，本研究进一步探究已知的尼古丁依赖（Nicotine Dependence, ND）基因是否与语言任务表现相关。本研究评估了此前被证实与尼古丁依赖相关的33个变异位点与语言损伤及语言能力的关联，发现ANKK1/DRD2与语言任务表现存在显著关联（p≤0.0003）。ANKK1内部位点的关联在另一独立的语言损伤病例对照队列中得到了重复验证，且ANKK1/DRD2可影响语言表现。更确切地说，本研究结果提示，产前环境因素可影响语言相关关键神经环路的宫内发育。本研究发现的ANKK1/DRD2关联，进一步证实了尼古丁相关通路及多巴胺信号传导在语言加工，尤其是语言理解与语音记忆过程中的关键作用。