title: Extensive natural variation for cellular hydrogen peroxide release is genetically controlled.
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.
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland. homa.attar@gmail.com
authors.forename: Homa
authors.initials: H
authors.lastname: Attar
authors.forename: Karen
authors.initials: K
authors.lastname: Bedard
authors.forename: Eugenia
authors.initials: E
authors.lastname: Migliavacca
authors.forename: Maryline
authors.initials: M
authors.lastname: Gagnebin
authors.forename: Yann
authors.initials: Y
authors.lastname: Dupré
authors.forename: Patrick
authors.initials: P
authors.lastname: Descombes
authors.forename: Christelle
authors.initials: C
authors.lastname: Borel
authors.forename: Samuel
authors.initials: S
authors.lastname: Deutsch
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.forename: Divya
authors.initials: D
authors.lastname: Mehta
authors.forename: Erich
authors.initials: E
authors.lastname: Wichmann
authors.forename: Jean Maurice
authors.initials: JM
authors.lastname: Delabar
authors.forename: Emmanouil T
authors.initials: ET
authors.lastname: Dermitzakis
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Krause
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Antonarakis
mesh_terms: D000328:Adult; D000368:Aged; D045744:Cell Line, Tumor; D015331:Cohort Studies; D008040:Genetic Linkage; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry* / Q000378:metabolism; D007231:Infant, Newborn; D008875:Middle Aged; D008957:Models, Genetic; D019255:NADPH Oxidases / Q000378:metabolism; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017382:Reactive Oxygen Species; D017422:Sequence Analysis, DNA
chemical_list: D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D019255:NADPH Oxidases