Sequencing of glutamatergic pathway genes in alcohol and nicotine co-dependence

描述（由申请人提供）：已表明遗传因素可能导致酒精和尼古丁共同依赖（AD+ND）。谷氨酸能通路在成瘾过程中起重要作用。全基因组研究已经证明谷氨酸能通路基因与吸烟相关性状和人类酒精反应变异相关。然而，AD+ND的遗传功能变异在很大程度上是未确定的。本研究的主要目的是鉴定AD+ND的神经递质能通路中潜在的功能变异，特别是频率低或作用弱的变异。我们选择了5个靶基因，包括GRIN 2B（谷氨酸受体，离子型，N-甲基D-天冬氨酸2B）、GRM 1（谷氨酸受体，代谢型1）、GRIK 1（谷氨酸受体，离子型，红藻氨酸1）、GLRA 2（甘氨酸受体，α 2）和NTRK 2（神经营养酪氨酸激酶，受体，2型）。这些区域将通过新的下一代测序方法在相对大的样本量（448例AD+ND病例和448例对照）中测序，即，靶向配对末端多重（TPM）测序。将在两个独立样本中测试这五个基因对AD+ND的单独效应和联合效应。如果成功，本研究将在AD+ND发病机制的研究方面取得重大进展，并可能有助于开发新的有效的AD+ND治疗和预防策略。此外，预期的研究结果可以提供一个更详细的遗传变异，特别是罕见的变异，在五个目标区域的地图，这将奠定基础，为未来的基因型-表型关系的研究。 公共卫生相关性：这个项目将寻找酒精和尼古丁共同依赖的因果位点，这将有助于我们更好地了解这种表型的生物学基础。预期的调查结果将大大有助于改善公共卫生。

DESCRIPTION (provided by applicant): It has been suggested that genetic factors may contribute to alcohol and nicotine co-dependence (AD+ND). Glutamatergic pathway plays important functional roles in addiction. Glutamatergic pathway genes have been demonstrated to be associated with smoking related traits and human variation in alcohol response by genome-wide studies. However, the genetic functional variants underlying AD+ND are largely unidentified. This study mainly aims to identify the potential functional variants underlying AD+ND in glutamatergic pathway, in particular, the variants with low frequencies or weak effects. We select five target genes, including GRIN2B (glutamate receptor, ionotropic, N-methyl D-aspartate 2B), GRM1 (glutamate receptor, metabotropic 1), GRIK1 (glutamate receptor, ionotropic, kainate 1), GLRA2 (glycine receptor, alpha 2) and NTRK2 (neurotrophic tyrosine kinase, receptor, type 2). These regions will be sequenced in a relatively large size of sample (448 AD+ND cases and 448 controls) by a novel next generation sequence approach, i.e., targeted paired-end multiplexed (TPM) sequencing. Both individual effects and joint effects of the five genes on AD+ND will be tested in two independent samples. If successful, this study would make big progress in the research on the mechanism of AD+ND and may be helpful in developing novel and effective treatment and prevention strategies for AD+ND. Furthermore, the expected findings could provide a much detailed map of genetic variants, in particular, rare variants, in the five target regions, which would lay a foundation for future investigation on genotype-phenotype relationship. PUBLIC HEALTH RELEVANCE: This proposed project will search for causal loci for alcohol and nicotine co-dependence, which will help us better understand the biological basis of this phenotype. The expected findings would significantly contribute to the improvement of public health.