Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
PLoS One. 2012;7(8):e43566. doi: 10.1371/journal.pone.0043566. Epub 2012 Aug 29.
Natural variation in DNA sequence contributes to individual differences in quantitative traits. While multiple studies have shown genetic control over gene expression variation, few additional cellular traits have been investigated. Here, we investigated the natural variation of NADPH oxidase-dependent hydrogen peroxide (H(2)O(2) release), which is the joint effect of reactive oxygen species (ROS) production, superoxide metabolism and degradation, and is related to a number of human disorders. We assessed the normal variation of H(2)O(2) release in lymphoblastoid cell lines (LCL) in a family-based 3-generation cohort (CEPH-HapMap), and in 3 population-based cohorts (KORA, GenCord, HapMap). Substantial individual variation was observed, 45% of which were associated with heritability in the CEPH-HapMap cohort. We identified 2 genome-wide significant loci of Hsa12 and Hsa15 in genome-wide linkage analysis. Next, we performed genome-wide association study (GWAS) for the combined KORA-GenCord cohorts (n = 279) using enhanced marker resolution by imputation (>1.4 million SNPs). We found 5 significant associations (p<5.00×10-8) and 54 suggestive associations (p<1.00×10-5), one of which confirmed the linked region on Hsa15. To replicate our findings, we performed GWAS using 58 HapMap individuals and ∼2.1 million SNPs. We identified 40 genome-wide significant and 302 suggestive SNPs, and confirmed genome signals on Hsa1, Hsa12, and Hsa15. Genetic loci within 900 kb from the known candidate gene p67phox on Hsa1 were identified in GWAS in both cohorts. We did not find replication of SNPs across all cohorts, but replication within the same genomic region. Finally, a highly significant decrease in H(2)O(2) release was observed in Down Syndrome (DS) individuals (p<2.88×10-12). Taken together, our results show strong evidence of genetic control of H(2)O(2) in LCL of healthy and DS cohorts and suggest that cellular phenotypes, which themselves are also complex, may be used as proxies for dissection of complex disorders.
自然 DNA 序列变异导致数量性状的个体差异。尽管多项研究表明基因表达变异受遗传控制，但很少有其他细胞特征得到研究。在这里，我们研究了 NADPH 氧化酶依赖性过氧化氢（H₂O₂释放）的自然变异，这是活性氧（ROS）产生、超氧化物代谢和降解的共同作用，与许多人类疾病有关。我们评估了基于家族的 3 代队列（CEPH-HapMap）和 3 个人群队列（KORA、GenCord、HapMap）中淋巴母细胞系（LCL）中 H₂O₂释放的正常变异。观察到个体间存在大量的差异，其中 45%与 CEPH-HapMap 队列中的遗传性相关。我们在全基因组连锁分析中发现了 Hsa12 和 Hsa15 的 2 个全基因组显著位点。接下来，我们使用增强标记分辨率的导入（>140 万 SNPs）对 KORA-GenCord 联合队列（n=279）进行了全基因组关联研究（GWAS）。我们发现了 5 个显著关联（p<5.00×10-8）和 54 个提示关联（p<1.00×10-5），其中一个关联证实了 Hsa15 上的连锁区域。为了复制我们的发现，我们使用 58 个 HapMap 个体和∼210 万个 SNPs 进行了 GWAS。我们鉴定了 40 个全基因组显著和 302 个提示 SNPs，并在两个队列中证实了 Hsa1、Hsa12 和 Hsa15 上的基因组信号。在 GWAS 中，在 Hsa1 上已知候选基因 p67phox 附近 900 kb 内的基因座被鉴定为与已知候选基因 p67phox 附近的基因座。我们没有在所有队列中发现 SNP 的复制，但在同一基因组区域内发现了复制。最后，唐氏综合征（DS）个体的 H₂O₂释放显著降低（p<2.88×10-12）。总之，我们的结果表明，LCL 中 H₂O₂的遗传控制具有很强的证据，并且表明自身也是复杂的细胞表型可以用作复杂疾病分析的替代物。
