Schulze T G, Detera-Wadleigh S D, Akula N, Gupta A, Kassem L, Steele J, Pearl J, Strohmaier J, Breuer R, Schwarz M, Propping P, Nöthen M M, Cichon S, Schumacher J, Rietschel M, McMahon F J
Unit on the Genetic Basis of Mood and Anxiety Disorders, National Institute of Mental Health, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD 20892-3719, USA.
Mol Psychiatry. 2009 May;14(5):487-91. doi: 10.1038/mp.2008.134. Epub 2008 Dec 16.
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 National Institute of Mental Health (NIMH) waves 1-4 (P=0.05; odds ratio (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 x 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 x 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 x marker interaction. Our findings strongly support ANK3 as a BD susceptibility gene and suggest true allelic heterogeneity.
最近的两份报告强调ANK3是双相情感障碍（BD）的一个易感基因。我们在两项独立样本的全基因组关联研究（GWAS）中首次报告了BD与ANK3标记rs9804190之间的关联（Baum等人，2008年）。随后，一项基于美国和英国样本的GWAS数据的荟萃分析报告了与另一个ANK3标记rs10994336的关联（Ferreira等人，2008年）。这些标记在基因中相距约340 kb。在这里，我们在其他样本中对这两个标记进行了检测，并描述了每个标记对BD风险的贡献。我们之前基于DNA池化在rs9804190处报告的发现，通过美国国立精神卫生研究所（NIMH）第1 - 4波（P = 0.05；优势比（OR）= 1.24）和德国样本（P = 0.0006；OR = 1.34）中的个体基因分型得到了证实。这种关联在一个名为NIMH第5波的独立美国样本中得到了重复（466例病例，212例对照；P = 0.017；OR = 1.38）。对所有三个样本进行的随机效应荟萃分析具有显著性（P = 3×10⁻⁶；OR = 1.32），且无异质性。rs10994336的个体基因分型在德国样本中显示出显著关联（P = 0.0001；OR = 1.70），在NIMH 1 - 4和NIMH 5样本中的OR值相似，但在P < 0.05水平上不显著。对所有三个样本的荟萃分析支持与rs10994336的关联（P = 1.7×10⁻⁵；OR = 1.54），同样无异质性。这两个标记之间几乎没有连锁不平衡。进一步的分析表明，每个标记对BD的贡献是独立的，不存在显著的标记×标记相互作用。我们的发现有力地支持ANK3作为一个BD易感基因，并表明存在真正的等位基因异质性。
