Family-based association analysis to finemap bipolar linkage peak on chromosome 8q24 using 2,500 genotyped SNPs and 15,000 imputed SNPs.

Multiple linkage and association studies have suggested chromosome 8q24 as a promising candidate region for bipolar disorder (BP). We performed a detailed association analysis assessing the contribution of common genetic variation in this region to the risk of BP. We analyzed 2,756 single nucleotide polymorphism (SNP) markers in the chromosome 8q24 region of 3,512 individuals from 737 families. In addition, we extended genotype imputation methods to family-based data and imputed 22,725 HapMap SNPs in the same region on 8q24. We applied a family-based method to test 15,552 high-quality genotyped or imputed SNPs for association with BP. Our association analysis identified the most significant marker (p = 4.80 × 10−5), near the gene encoding potassium voltage-gated channel KQT-like protein (KCNQ3). Other marginally significant markers were located near adenylate cyclase 8 (ADCY8) and ST3 beta-galactoside alpha-2,3-sialyltransferase 1 (ST3GAL1). We developed an approach to apply MACH imputation to family-based data, which can increase the power to detect association signals. Our association results showed suggestive evidence of association of BP with loci near KCNQ3, ADCY8, and ST3GAL1. Consistent with genes identified by genome-wide association studies for BP, our results are consistent with the involvement of ion channelopathy in BP pathogenesis. However, common variants are insufficient to explain linkage findings in 8q24; other genetic variations should be explored.

多项连锁和关联研究表明，染色体8q24是双相情感障碍（BP）的一个有潜力的候选区域。我们进行了详细的关联分析，以评估该区域常见的基因变异对双相情感障碍风险的影响。 我们分析了来自737个家庭的3512名个体的染色体8q24区域的2756个单核苷酸多态性（SNP）标记。此外，我们将基因型填补方法扩展到基于家庭的数据，并对8q24同一区域的22725个国际人类基因组单体型图（HapMap）SNP进行了填补。我们应用一种基于家庭的方法，对15552个高质量的基因分型或填补的SNP与双相情感障碍的关联进行了检测。 我们的关联分析确定了最显著的标记（p = 4.80×10⁻⁵），它靠近编码钾电压门控通道KQT样蛋白（KCNQ3）的基因。其他具有边缘显著性的标记位于腺苷酸环化酶8（ADCY8）和ST3 β -半乳糖苷α -2,3 -唾液酸转移酶1（ST3GAL1）附近。 我们开发了一种将MACH填补应用于基于家庭的数据的方法，这种方法可以提高检测关联信号的能力。我们的关联结果显示出双相情感障碍与KCNQ3、ADCY8和ST3GAL1附近基因座有关联的提示性证据。与双相情感障碍的全基因组关联研究中确定的基因一致，我们的结果与离子通道病参与双相情感障碍的发病机制相符。然而，常见变异不足以解释8q24中的连锁发现；应该探索其他基因变异。