Meta-analysis shows strong positive association of the neuregulin 1 (NRG1) gene with schizophrenia
Meta-analysis shows strong positive association of the neuregulin 1 (NRG1) gene with schizophrenia
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DOI：
10.1093/hmg/ddl122
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发表时间：
2006-06-15
影响因子：
3.5
通讯作者：
He, Lin
中科院分区：
文献类型：
--
作者：
Li, Dawei;Collier, David A.;He, Lin
染色体8 p22-p11在几次全基因组扫描中被确定为精神分裂症的位点，并通过对已发表的连锁数据的荟萃分析得到证实。使用扩展的冰岛谱系进行的系统性精细作图确定了基因neuregulin 1（NRG 1）中的相关单倍型，也称为heuregulin，神经胶质生长因子，NDF 43和ARIA。一个290 kb的核心风险单倍型在5'端的基因（HAP（ICE）），定义为5个SNP和两个微卫星多态性被发现与精神分裂症在冰岛和苏格兰人口。随后的一些独立研究试图复制这种关联，虽然有些研究取得了成功，但相关的单倍型并不总是HAP（ICE）。此外，还没有发现明显的功能性或致病性变异，该基因与精神分裂症之间的关系仍然没有定论。为了调和这些相互矛盾的研究结果，并给出一个全面的图片这个重要的基因的遗传结构，我们进行了荟萃分析，13个已发表的基于人群和基于家庭的关联研究到2005年11月。我们分析了SNP标记SNP 8 NRG 241930、SNP 8 NRG 243177、SNP 8 NRG 221132和SNP 8 NRG 221533以及微卫星标记4781314-848、420 M9 -1395的数据。在这些研究中，发现所有六种多态性都有很强的正相关。单倍型分析也显示了在合并的国际人群中的显著关联（OR = 1.22，95%CI 1.15-1.3，P = 8 × 10（-10））。在亚洲人群中，风险单倍型集中在两个微卫星标记4781314-848、420 M9 -1395（单倍型块13）周围，而在高加索人群中，风险单倍型集中在其余四个SNP标记（单倍型块A）周围。这项荟萃分析支持NRG 1参与精神分裂症的发病机制，但在高加索人和亚洲人中，两个不同但相邻的单倍型块之间存在关联。
Chromosome 8p22-p11 has been identified as a locus for schizophrenia in several genome-wide scans and confirmed by meta-analysis of published linkage data. Systematic fine mapping using extended Icelandic pedigrees identified an associated haplotype in the gene neuregulin 1 (NRG1), also known as heuregulin, glial growth factor, NDF43 and ARIA. A 290 kb core at risk haplotype at the 5' end of the gene (HAP(ICE)), defined by five SNPs and two microsatellite polymorphisms was found to be associated with schizophrenia in the Icelandic and Scottish populations. A number of subsequent independent studies have attempted to replicate the association, and while some have been successful, the associated haplotype is not always HAP(ICE). Furthermore, no obviously functional or pathogenic variants have been identified, and the relationship between the gene and schizophrenia has remained inconclusive. To reconcile these conflicting findings and to give a comprehensive picture of the genetic architecture of this important gene, we performed a meta-analysis of 13 published population-based and family-based association studies up to November 2005. We analysed data from the SNP markers SNP8NRG241930, SNP8NRG243177, SNP8NRG221132 and SNP8NRG221533, and the microsatellite markers 4781314-848, 420M9-1395. Across these studies, strong positive association was found for all six polymorphisms. The haplotype analysis also showed significant association in the pooled international populations (OR = 1.22, 95% Cl 1.15-1.3, P = 8 x 10(-10)). In Asian populations, the risk haplotype was focused around the two microsatellite markers, 4781314-848, 420M9-1395 (haplotype block 13), and in Caucasian populations with the remaining four SNP markers (haplotype block A). This meta-analysis supports the involvement of NRG1 in the pathogenesis of schizophrenia, but with association between two different but adjacent haplotypes blocks in the Caucasian and Asian populations.