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Extensive natural variation for cellular hydrogen peroxide release is genetically controlled

Contributors

Attar Cohen, Homa; Bedard, Karen; Migliavacca Voeffray, Eugenia Linda; Gagnebin, Maryline; Dupre, Yann; Descombes, Patrick; Borel, Christelle; Deutsch Escalante, Samuel; Prokisch, Holger; Meitinger, Thomas; Mehta, Divya; Wichmann, Erich; Delabar, Jean Maurice; Dermitzakis, Emmanouil; Krause, Karl-Heinz; Antonarakis, Stylianos

Published in

PloS one, vol. 7, no. 8, e43566

Publication date

2012

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

  • Adult
  • Aged
  • Cell Line, Tumor
  • Cohort Studies
  • Genetic Linkage
  • Genome, Human
  • Genome-Wide Association Study
  • Humans
  • Hydrogen Peroxide/chemistry/metabolism
  • Infant, Newborn
  • Middle Aged
  • Models, Genetic
  • NADPH Oxidase/metabolism
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Reactive Oxygen Species
  • Sequence Analysis, DNA

UNIGE affiliation entities

UNIGE research groups

Funding

  • Autre - Jeantet

Citation (ISO format)

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. doi: 10.1371/journal.pone.0043566

Main files (1)

Article (Published version)
CC BY

Identifiers

Journal ISSN

1932-6203
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564downloads

Technical informations

Creation

15/12/2013 23:43:00

First validation

15/12/2013 23:43:00

Update

14/03/2023 20:43:20

Status update

14/03/2023 20:43:20

Last indexation

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