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

描述（由申请人提供）：遗传因素可能导致酒精和尼古丁的共同依赖（AD+ND）。谷氨酸通路在成瘾过程中起着重要的功能作用。通过全基因组研究，谷氨酸途径基因已被证明与吸烟相关的性状和人类对酒精反应的变异有关。然而，AD+ND的遗传功能变异在很大程度上是未知的。本研究主要旨在发现谷氨酸能通路中AD+ND潜在的功能变异，特别是低频或弱作用的变异。我们选择了五个靶基因，包括GRIN2B（谷氨酸受体，嗜离子性，n -甲基d -天冬氨酸2B）、GRM1（谷氨酸受体，代谢性1）、GRIK1（谷氨酸受体，嗜离子性，kainate 1）、GLRA2（甘氨酸受体，α 2）和NTRK2（神经营养酪氨酸激酶受体，2型）。这些区域将在相对较大的样本（448例AD+ND病例和448例对照）中通过一种新的下一代测序方法进行测序，即靶向对端多路（TPM）测序。五个基因对AD+ND的个体效应和联合效应将在两个独立的样本中进行测试。如果成功，本研究将在AD+ND的机制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更详细的遗传变异图谱，特别是罕见变异，在五个目标区域，这将为未来的基因型-表型关系的研究奠定基础。

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.