Institute of Human Genetics, University of Bonn, Bonn, Germany.
Am J Med Genet B Neuropsychiatr Genet. 2010 Jun 5;153B(4):878-84. doi: 10.1002/ajmg.b.31051.
Strong evidence of linkage between chromosomal region 6q16-q22 and bipolar affective disorder (BPAD) has previously been reported. We conducted a systematic association mapping of the 6q-linkage interval using 617 SNP markers in a BPAD case-control sample of German descent (cases = 330, controls = 325). In this screening step, 46 SNPs showed nominally significant BPAD-association (P-values between 0.0007 and 0.0484). Although none of the 46 SNPs survived correction for multiple testing, they were genotyped in a second and ethnically matched BPAD sample (cases = 328, controls = 397). At the melanin-concentrating-hormone-receptor-2 (MCHR2) gene, we found nominal association in both the initial and second BPAD samples (combined P = 0.008). This finding was followed up by the genotyping of 17 additional MCHR2-SNPs in the combined sample in order to define our findings more precisely. We found that the MCHR2-locus can be divided into three different haplotype-blocks, and observed that the MCHR2-association was most pronounced in BPAD male patients with psychotic symptoms. In two neighboring blocks, putative risk-haplotypes were found to be 7% more frequent in patients (block II: 23.3% vs. 16.2%, P = 0.005, block III: 39.2% vs. 32.0%, P = 0.024), whereas the putative protective haplotypes were found to be 5-8% less frequent in patients (block II: 11.6% vs. 16.4%, P = 0.041, block III: 30.0% vs. 38.8%, P = 0.007). The corresponding odds ratios (single-marker analysis) ranged between 1.25 and 1.46. Our findings may indicate that MCHR2 is a putative risk factor for BPAD. These findings should be interpreted with caution and replicated in independent BPAD samples.
先前已有研究报道，6 号染色体区域 6q16-q22 与双相情感障碍（BPAD）之间存在明显的连锁关系。我们使用德国血统的 BPAD 病例对照样本（病例=330，对照=325）中的 617 个 SNP 标记，对 6q 连锁区间进行了系统的关联作图。在这个筛选步骤中，46 个 SNP 显示出与 BPAD 有显著的关联（P 值在 0.0007 到 0.0484 之间）。尽管没有一个 SNP 在多重测试校正后仍然显著，但它们在第二个和种族匹配的 BPAD 样本（病例=328，对照=397）中进行了基因分型。在黑色素浓缩激素受体-2（MCHR2）基因中，我们在初始和第二个 BPAD 样本中都发现了名义上的关联（联合 P=0.008）。这一发现促使我们在合并样本中对 17 个额外的 MCHR2-SNP 进行了基因分型，以更精确地定义我们的发现。我们发现 MCHR2 基因座可以分为三个不同的单倍型块，并且观察到 MCHR2 与具有精神病症状的 BPAD 男性患者的关联最为显著。在两个相邻的块中，发现潜在的风险单倍型在患者中更为常见，分别为 7%（块 II：23.3%比 16.2%，P=0.005，块 III：39.2%比 32.0%，P=0.024），而潜在的保护单倍型在患者中则更为少见，分别为 5-8%（块 II：11.6%比 16.4%，P=0.041，块 III：30.0%比 38.8%，P=0.007）。相应的比值比（单标记分析）在 1.25 到 1.46 之间。我们的发现可能表明 MCHR2 是 BPAD 的一个潜在风险因素。这些发现应该谨慎解释，并在独立的 BPAD 样本中进行复制。
