Fan J B, Sklar P
Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Charlestown, MA 02129, and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Mol Psychiatry. 2005 Oct;10(10):928-38, 891. doi: 10.1038/sj.mp.4001690.
The serotonin transporter gene (SLC6A4) is a candidate gene for schizophrenia based on serotonin transporter's crucial role in serotonergic neurotransmission. However, association studies have produced conflicting results regarding the association between two common SLC6A4 gene polymorphisms, the promoter insertion/deletion (5-HTTLPR) and the intron 2 VNTR (STin2 VNTR) polymorphisms, and schizophrenia susceptibility. To further elucidate the putative association between the two SLC6A4 gene polymorphisms and schizophrenia susceptibility, we performed a meta-analysis based on all original published association studies between schizophrenia and the 5-HTTLPR and STin2 VNTR polymorphisms published before April 2004. Our analyses showed no statistically significant evidence for the association between the Short allele of the 5-HTTLPR polymorphism and schizophrenia (random-effects pooled odds ratio (OR)=0.99, 95% Confidence Interval (CI)=0.92-1.07, Z=-0.23, P=0.82) from 19 population-based association studies consisting of 2990 case and 3875 control subjects. However, highly significant evidence for association between the STin2.12 allele of the STin2 VNTR polymorphism (random-effects pooled OR=1.24, 95% CI=1.11-1.38, Z=3.82, P=0.00014) and schizophrenia was found from 12 population-based association studies consisting of 2177 cases and 2369 control subjects. Our meta-analysis suggests that the STin2.12 allele of the STin2 VNTR polymorphism is likely a risk factor for schizophrenia susceptibility. Our data imply that following completion of the International HapMap Project, a comprehensive evaluation of a set of markers that fully characterize the linkage disequilibrium relationships at the SLC6A4 gene should be tested in large well-characterized clinical samples in order to understand the role of this gene in schizophrenia susceptibility.
基于血清素转运体在血清素能神经传递中的关键作用，血清素转运体基因（SLC6A4）是精神分裂症的一个候选基因。然而，关于SLC6A4基因的两个常见多态性，即启动子插入/缺失（5-HTTLPR）和内含子2可变数目串联重复序列（STin2 VNTR）多态性与精神分裂症易感性之间的关联研究结果相互矛盾。为了进一步阐明这两个SLC6A4基因多态性与精神分裂症易感性之间的假定关联，我们基于2004年4月之前发表的所有关于精神分裂症与5-HTTLPR和STin2 VNTR多态性的原始关联研究进行了一项荟萃分析。我们的分析显示，来自19项基于人群的关联研究（包括2990例病例和3875例对照）的结果表明，5-HTTLPR多态性的短等位基因与精神分裂症之间无统计学显著关联（随机效应合并比值比（OR）=0.99，95%置信区间（CI）=0.92 - 1.07，Z = -0.23，P = 0.82）。然而，来自12项基于人群的关联研究（包括2177例病例和2369例对照）的结果发现，STin2 VNTR多态性的STin2.12等位基因与精神分裂症之间存在高度显著关联（随机效应合并OR = 1.24, 95% CI = 1.11 - 1.38, Z = 3.82, P = 0.00014）。我们的荟萃分析表明，STin2 VNTR多态性的STin2.12等位基因可能是精神分裂症易感性的一个危险因素。我们的数据表明，在国际人类基因组单体型图计划完成之后，应该在特征明确的大型临床样本中对一组能够全面表征SLC6A4基因连锁不平衡关系的标记进行综合评估，以便了解该基因在精神分裂症易感性中的作用。
