Extensive Natural Variation for Cellular Hydrogen Peroxide Release Is Genetically Controlled

Attar, Homa, Bedard, Karen, Migliavacca, Eugenia, Gagnebin, , Maryline, Dupre, Yann, Descombes, Patrick, Borel, Christelle, Deutsch, Samuel, Prokisch, Holger, Meitinger, Thomas, Mehta, Divya, Wichmann, Erich, Delabar, Jean Maurice, Dermitzakis, Emmanouil T., Krause, Karl-Heinz and Antonarakis, Stylianos E. (2012) Extensive Natural Variation for Cellular Hydrogen Peroxide Release Is Genetically Controlled. PLoS One, 7 8: e43566-e43566. doi:10.1371/journal.pone.0043566

Author Attar, Homa
Bedard, Karen
Migliavacca, Eugenia
Gagnebin, , Maryline
Dupre, Yann
Descombes, Patrick
Borel, Christelle
Deutsch, Samuel
Prokisch, Holger
Meitinger, Thomas
Mehta, Divya
Wichmann, Erich
Delabar, Jean Maurice
Dermitzakis, Emmanouil T.
Krause, Karl-Heinz
Antonarakis, Stylianos E.
Title Extensive Natural Variation for Cellular Hydrogen Peroxide Release Is Genetically Controlled
Journal name PLoS One   Check publisher's open access policy
ISSN 1932-6203
Publication date 2012-08-29
Year available 2012
Sub-type Article (original research)
DOI 10.1371/journal.pone.0043566
Open Access Status DOI
Volume 7
Issue 8
Start page e43566
End page e43566
Total pages 13
Place of publication San Francisco, CA United States
Publisher Public Library of Science
Collection year 2012
Language eng
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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Queensland Brain Institute Publications
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Citation counts: TR Web of Science Citation Count  Cited 3 times in Thomson Reuters Web of Science Article | Citations
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Created: Mon, 27 Oct 2014, 14:34:23 EST by Sylvie Pichelin on behalf of Queensland Brain Institute