A hierarchical and modular approach to the discovery of robust associations in genome-wide association studies from pooled DNA samples

Sebastiani, Paola; Zhao, Zhenming; Abad‐Grau, María M.; Riva, Alberto; Hartley, Stephen W.; Sedgewick, Amanda; Doria, Alessandro; Montano, Monty; Melista, Efthymia; Terry, Dellara F.; Perls, Thomas T.; Steinberg, Martin H.; Baldwin, Clinton T.

doi:10.1186/1471-2156-9-6

Cited by 26 publications

(18 citation statements)

References 58 publications

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“…However, we might speculate that the VEGFR2 472Gln allele is associated with enhanced skeletal muscle tissue responsiveness to VEGF and increased angiogenesis. Recently, two studies have reported that the functional His472Gln polymorphism of the VEGFR2 gene inXuences the eYciency of VEGF binding to VEGFR2 Zhang et al 2007) and is associated with several clinical phenotypes such as exceptional longevity, coronary heart disease, intracerebral haemorrhage, breast cancer and long-term aortocoronary saphenous vein graft patency (Ellis et al 2007;Försti et al 2007;Wang et al 2007;Zhang et al 2007;Sebastiani et al 2008). Collectively, our Wndings suggest that the observed associations are mediated through alterations in VEGFR2 activity.…”

Section: Discussionmentioning

confidence: 48%

“…However, associations between variations in the VEGFR2 gene (approved symbol: KDR) on elite athlete status and related phenotypes have not yet been investigated. One of the potential functional polymorphisms of the VEG-FR2 gene is the rs1870377 T/A variant (exon 11), which determines a histidine (His) to glutamine (Gln) substitution of the receptor and is associated with several clinical phenotypes (Ellis et al 2007;Försti et al 2007;Wang et al 2007;Zhang et al 2007;Sebastiani et al 2008). This polymorphism is located in the Wfth NH 2 -terminal Ig-like domain within the extracellular region, which is important for ligand binding.…”

Section: Introductionmentioning

confidence: 99%

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Association of the VEGFR2 gene His472Gln polymorphism with endurance-related phenotypes

et al. 2009

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Vascular endothelial growth factor receptor 2 (VEGFR2) is essential to induce the full spectrum of VEGF angiogenic responses to aerobic training. In the present study, we examined the impact of the functional His472Gln polymorphism of the VEGFR2 gene on elite athlete status, endurance performance and muscle fibre type composition. Four hundred and seventy-one Russian athletes were prospectively stratified into four groups according to event duration, distance and type of activity, covering a spectrum from the more endurance-oriented to the more power-oriented. VEGFR2 genotype and allele frequencies were compared to 603 controls. To examine the association between VEGFR2 genotype and fibre type composition, vastus lateralis muscle biopsies were obtained from 45 physically active healthy men and 23 all-round speed skaters. In addition, 76 competitive rowers performed incremental endurance exercise to allow analysis of genotype associations with exercise responses. We found that the frequency of the VEGFR2 472Gln allele was significantly higher in endurance-oriented athletes compared to controls (36.8 vs. 27.4%, P = 0.0006). Relative VO(2max) was significantly greater in the VEGFR2 472Gln allele carriers compared with the His/His homozygotes of the sub-elite female rower group only. Genotype-specific differences were found for the proportion of slow-twitch fibres in both athletes and controls, which was approximately 10.1 and approximately 7.4% higher in the His/Gln and Gln/Gln genotypes than in the His/His genotype group, respectively. In conclusion, we have shown for the first time that variation in the VEGFR2 gene is associated with elite athlete status, endurance performance of female rowers and muscle fibre type composition.

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Section: Discussionmentioning

confidence: 48%

Section: Introductionmentioning

confidence: 99%

Association of the VEGFR2 gene His472Gln polymorphism with endurance-related phenotypes

et al. 2009

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“…17,22 These studies demonstrated that even with relatively small samples, pooled methods as described can approach almost 70% sensitivity with 100 subjects in each group. 26 There currently are no formal statistical methods that would allow the calculation of specific numbers of patients needed for pool-based GWAS. Thus, the calculations of the approximate power statistics and sample size were performed based on the method described by Skol et al (2006) and using their CaTS-Power Calculator for Two Stage Association Studies.…”

Section: Study Participantsmentioning

confidence: 99%

Genome-wide Association Study Using Pooled DNA to Identify Candidate Markers Mediating Susceptibility to Postoperative Nausea and Vomiting

et al. 2011

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Background: A family history has been established as a risk factor for postoperative nausea and vomiting (PONV), but the identities of susceptibility genes remain unknown. The goal of this study was to identify the genetic loci that may contribute to PONV susceptibility in an adult population. Methods:The authors performed a genome-wide association study involving pooling of DNA obtained from 122 patients with severe PONV and 129 matched controls. Each pool was hybridized to a single nucleotide polymorphism (SNP) microarray, and probe intensity was used to predict allele frequency. Differences in allele frequency between SNP in the PONV and control groups were ranked after accounting for the pooling error. The highest ranking SNPs were selected for individual genotyping in the subjects from whom the DNA pool was comprised and in the new verification cohort consisting of 208 subjects (104 PONV patients and 104 controls). Results: The authors identified 41 SNP targets showing substantial difference in allelic frequency between pools. These markers were first genotyped in the individual DNA samples from which the pools were comprised. The authors observed evidence for an association between PONV and 19 different loci in the genome. In the separate verification cohort, the association with PONV was observed for four SNPs. This association remained significant after correcting

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“…In a recent study of human centenarians by our group, the RNA-editing genes ADARB1 (21q22.3), and ADARB2 (10p15.3) emerged as candidate genes associated with exceptional longevity in a screening based on a new DNA pooling approach (Sebastiani et al, 2008). These preliminary data were then validated using individually genotyped data from four different centenarian cohorts for a larger number of SNPs and a total sample size (2105 subjects, 3044 controls.…”

Section: The Relevance Of Rna Surveillance To Aging Inflammation mentioning

confidence: 99%

RNA surveillance—An emerging role for RNA regulatory networks in aging

Montano¹,

Long²

2011

Ageing Research Reviews

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In this review, we describe recent advances in the field of RNA regulatory biology and relate these advances to aging science. We introduce a new term, RNA surveillance, an RNA regulatory process that is conserved in metazoans, and describe how RNA surveillance represents molecular cross-talk between two emerging RNA regulatory systems – RNA interference and RNA editing. We discuss how RNA surveillance mechanisms influence mRNA and microRNA expression and activity during lifespan. Additionally, we summarize recent data from our own laboratory linking the RNA editor, ADAR, with exceptional longevity in humans and lifespan in C. elegans. We present data showing that transcriptional knockdown of RNA interference restores lifespan losses in the context of RNA editing defects, further suggesting that interaction between these two systems influences lifespan. Finally, we discuss the implications of RNA surveillance for sarcopenia and muscle maintenance, as frailty is a universal feature of aging. We end with a discussion of RNA surveillance as a robust regulatory system that can change in response to environmental stressors and represents a novel axis in aging science.

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A hierarchical and modular approach to the discovery of robust associations in genome-wide association studies from pooled DNA samples

Abstract: Background: One of the challenges of the analysis of pooling-based genome wide association studies is to identify authentic associations among potentially thousands of false positive associations.

Cited by 26 publications

References 58 publications

Association of the VEGFR2 gene His472Gln polymorphism with endurance-related phenotypes

Association of the VEGFR2 gene His472Gln polymorphism with endurance-related phenotypes

Genome-wide Association Study Using Pooled DNA to Identify Candidate Markers Mediating Susceptibility to Postoperative Nausea and Vomiting

RNA surveillance—An emerging role for RNA regulatory networks in aging

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