Pathway Analysis Suggest the Calcium Signaling Pathway Associated with Alcohol Dependence
作者: 郭艳芳 ：南方医科大学基础医学院，广州;
Abstract: Background: Alcohol dependence (AD) is a serious and common public health problem. A large number of association studies were conducted to identify susceptibility genes of AD, but efforts to generate an integrate view of accumulative genetic variants and pathways under alcohol drinking are lacking. Methods: We applied enrichment gene set analysis to existing genetic association results to identify pertinent pathways to alcohol dependence in this study. A total of 1438 SNPs (P < 1.0 ´ 10−3) associated to alcohol drinking related-traits have been collected from 31 studies. Results: The calcium signaling pathway (hsa04020) showed the most significant enrichment of associations (21 genes) to alcohol consumption phenotypes (P = 5.4 ´ 10−5), achieving bonferroni P value of 0.8 ´ 10−3 and FDR value of 0.6 ´ 10−2, respectively. Interestingly, the calcium signaling pathway was previously found to be essential to regulate brain function. Genes in this pathway link to a depressive effect of alcohol consumption on the body. Conclusions: Our findings, together with previous biological evidence suggest the importance of gene polymorphisms of calcium signaling pathway to alcohol dependence susceptibility.
文章引用: 郭艳芳 (2014) 通路分析提示钙信号转导通路与酒精依赖关联。 生物医学， 4， 1-6. doi: 10.12677/HJBM.2014.41001
 Rietschel, M. and Treutlein, J. (2012) The genetics of alcohol dependence. Annals of the New York Academy of Sciences, 8, 151-157.
 Kimura, M. and Higuchi, S. (2011) Genetics of alcohol dependence. Psychiatry and Clinical Neurosciences, 65, 213-225.
 McKay, J.D., Truong, T., Gaborieau, V. et al. (2011) A genomewide association study of upper aerodigestive tract cancers conducted within the INHANCE consortium. PLOS Genetics, 7, e1001333.
 Takeuchi, F., Isono, M., Nabika, T., et al. (2011) Confirmation of ALDH2 as a Major locus of drinking behavior and of its variants regulating multiple metabolic phenotypes in a Japanese population. Circulation Journal, 75, 911-918.
 Zakhari, S. (2006) Overview: How is alcohol metabolized by the body? Alcohol Research & Health, 29, 245-254.
 Wang, K., Li, M. and Hakonarson, H. (2010) Analysing biological pathways in genome-wide association studies. Nature Reviews Genetics, 11, 843-854.
 Li, M.J., Wang, P., Liu, X., et al. (2012) GWASdb: A database for human genetic variants identified by genome-wide association studies. Nucleic Acids Research, 40, D1047-D1054.
 Dayem, U.A.Z., Lemoine, N.R., Chelala, C. (2012) SNPnexus: A web server for functional annotation of novel and publicly known genetic variants (2012 update). Nucleic Acids Research, 40, W65-W70.
 Huang da, W., Sherman, B.T. and Lempicki, R.A. (2009) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nature Protocols, 4, 44-57.
 Yuan, H.Y., Chiou, J.J., Tseng, W.H., et al. (2006) FASTSNP: An always up-to-date and extendable service for SNP function analysis and prioritization. Nucleic Acids Research, 34, W635W641.
 Joslyn, G., Ravindranathan, A., Brush, G., et al. (2010) Human variation in alcohol response is influenced by variation in neuronal signaling genes. Alcoholism: Clinical and Experimental Research, 34, 800-812.
 Uhl, G.R., Drgon, T., Johnson, C., et al. (2008) Higher order addiction molecular genetics: convergent data from genomewide association in humans and mice. Biochemical Pharmacology, 75, 98-111.
 Kendler, K.S., Kalsi, G., Holmans, P.A., et al. (2011) Genome wide association analysis of symptoms of alcohol dependence in the molecular genetics of schizophrenia (MGS2) control sample. Alcoholism: Clinical and Experimental Research, 35, 963-975.
 Reimers, M.A., Riley, B.P., Kalsi, G., et al. (2012) Pathway based analysis of genotypes in relation to alcohol dependence. The Pharmacogenomics Journal, 12, 342-348.
 Biernacka, J.M., Geske, J., Jenkins, G.D., et al. (2013) Genome-wide gene-set analysis for identification of pathways associated with alcohol dependence. The International Journal of Neuropsychopharmacology, 16, 271-278.
 Dodd, J.R., Birch, N.P., Waldvogel, H.J., et al. (2010) Functional and immunocytochemical characterization of the creatine transporter in rat hippocampal neurons. Journal of Neurochemistry, 115, 684-693.
 Popoli, M., Gennarelli, M. and Racagni, G. (2002) Modulation of synaptic plasticity by stress and antidepressants. Bipolar Disorders, 4, 166-182.
 Kao, C.F., Jia, P., Zhao, Z., et al. (2012) Enriched pathways for major depressive disorder identified from a genome-wide association study. The International Journal of Neuropsychopharmacology, 15, 1401-1411.