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Extensive natural variation for cellular hydrogen peroxide release is genetically controlled

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Published in PLOS ONE. 2012, vol. 7, no. 8, p. e43566
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 (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.
Keywords AdultAgedCell Line, TumorCohort StudiesGenetic LinkageGenome, HumanGenome-Wide Association StudyHumansHydrogen Peroxide/chemistry/metabolismInfant, NewbornMiddle AgedModels, GeneticNADPH Oxidase/metabolismPhenotypePolymorphism, Single NucleotideReactive Oxygen SpeciesSequence Analysis, DNA
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PMID: 22952707
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Article (Published version) (575 Kb) - public document Free access
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Research groups Population Genomics and Genetics of Complex Traits (892)
Pathologie Moléculaire de la Trisomie 21 et le Génome Humain (248)
Project Jeantet
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ATTAR COHEN, Homa et al. Extensive natural variation for cellular hydrogen peroxide release is genetically controlled. In: PLOS ONE, 2012, vol. 7, n° 8, p. e43566. https://archive-ouverte.unige.ch/unige:32154

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Deposited on : 2013-12-16

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