Two variants in Ankyrin 3 (ANK3) are independent genetic risk factors for bipolar disorder.
Two variants in Ankyrin 3 (ANK3) are independent genetic risk factors for bipolar disorder.
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DOI：
10.1038/mp.2008.134
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发表时间：
2009-05
影响因子：
11
通讯作者：
中科院分区：
文献类型：
--
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最近的两份报告强调ANK 3是双相情感障碍（BD）的易感基因。我们在两个独立样本的全基因组关联研究（GWAS）中首次报道了BD和ANK 3标记rs 9804190之间的关联（Baum et al 2008）。随后，基于美国和英国样本的GWAS数据的荟萃分析报告了与不同ANK 3标记rs 10994336的相关性（Ferreira et al 2008）。这些标记在基因中相距约340 kb。在这里，我们在额外的样本中测试这两种标志物，并表征每种标志物对BD风险的贡献。我们先前报告的rs 9804190研究结果（基于DNA合并）通过NIMH Waves 1-4（p=0.050; OR=1.24）和德国（p=0.0006; OR=1.34）样本中的个体基因分型得到证实。这种关联在一个独立的美国样本中被复制，称为NIMH Wave 5（466例，212例对照; p=0.017; OR=1.38）。所有三个样本的随机效应荟萃分析均具有显著性（p = 3 × 10−6; OR=1.32），无异质性。rs 10994336的个体基因分型揭示了德国样本中的显著关联（p=0.0001; OR=1.70），并且在NIMH 1-4和NIMH 5样本中的相似OR在p<0.05水平上不显著。所有三个样本的荟萃分析支持与rs 10994336的相关性（p=1.7 × 10−5; OR=1.54），同样没有异质性。这两个标记之间几乎没有连锁不平衡。进一步分析表明，每个标记独立地贡献BD，没有显著的标记×标记相互作用。我们的研究结果强烈支持ANK 3作为BD易感基因，并建议真正的等位基因异质性。
Two recent reports have highlighted ANK3 as a susceptibility gene for bipolar disorder (BD). We first reported association between BD and the ANK3 marker rs9804190 in a genome-wide association study (GWAS) of two independent samples (Baum et al 2008). Subsequently, a meta-analysis of GWAS data based on samples from the US and the UK reported association with a different ANK3 marker, rs10994336 (Ferreira et al 2008). The markers lie about 340 kb apart in the gene. Here we test both markers in additional samples and characterize the contribution of each marker to BD risk. Our previously reported findings at rs9804190, which had been based on DNA pooling, were confirmed by individual genotyping in the NIMH Waves 1-4 (p=0.050; OR=1.24) and German (p=0.0006; OR=1.34) samples. This association was replicated in an independent US sample known as NIMH Wave 5 (466 cases, 212 controls; p=0.017; OR=1.38). A random-effects meta-analysis of all three samples was significant (p = 3 × 10−6; OR=1.32), with no heterogeneity. Individual genotyping of rs10994336 revealed a significant association in the German sample (p=0.0001; OR=1.70), and similar ORs in the NIMH 1–4 and NIMH 5 samples that were not significant at the p<0.05 level. Meta-analysis of all three samples supported an association with rs10994336 (p=1.7 × 10−5; OR=1.54), again with no heterogeneity. There was little linkage disequilibrium between the two markers. Further analysis suggested that each marker contributed independently to BD, with no significant marker × marker interaction. Our findings strongly support ANK3 as a BD susceptibility gene and suggest true allelic heterogeneity.
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