Abstract
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 (H2O2 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 H2O2 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 H2O2 release was observed in Down Syndrome (DS) individuals (p<2.88×10−12). Taken together, our results show strong evidence of genetic control of H2O2 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.
Highlights
Recent genome-wide association studies (GWAS) using clinical phenotypes have identified a large number of DNA polymorphisms that convey an increased risk for common diseases
KORA is a cohort of newly established lymphoblastoid cell lines (LCL) derived from unrelated healthy adults, GenCord is a cohort of newly established LCL derived from unrelated newborns, and HapMap is part of a threegenerational sample cohort, from which unrelated LCL from healthy adults were used for genome wide association (GWA) analysis
The phenotypic distribution of H2O2 release in the Down Syndrome (DS) cohort differed from all other healthy cohorts, with a significantly different distribution compared to the HapMap (Wilcoxon rank sum test, p,2.88610212), the GenCord (p,3.1161029), and the KORA cohort (p,5.3561029, Figure 1)
Summary
Recent genome-wide association studies (GWAS) using clinical phenotypes have identified a large number of DNA polymorphisms that convey an increased risk for common diseases. Identified genetic loci, explain only a small fraction of the overall observed phenotypic variability even when assessing very large sample sizes [1,2,3,4,5,6,7,8] owing to biological complexity [9] and low penetrance of common genomic variants [10]. Small-scale studies (,100 individuals) indicate that gene expression is genetically controlled [11,12,13] emphasizing the direct link between phenotypic and genotypic variation. Despite these findings, how individual genes affect disease mechanisms remains poorly understood. Our study will explore hydrogen peroxide (H2O2) release which is associated with multiple diseases as a proxy for a complex phenotype
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