Application of pooled genotyping to scan candidate regions for association with HDL cholesterol levels

Hinds, David A.; Seymour, Albert B.; Durham, L. Kathryn; Banerjee, Poulabi; Ballinger, Dennis G.; Milos, Patrice M.; Cox, David; Thompson, John F.; Frazer, Kelly A.

doi:10.1186/1479-7364-1-6-421

Cited by 87 publications

(61 citation statements)

References 28 publications

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“…50,51 However, in the two cases where whole genome association has been attempted (that is, in memory 52 and mild mental impairment 53 ), the yields have been low, that is, in both cases only one locus was considered significant.…”

Section: Discussionmentioning

confidence: 99%

A whole genome association study of neuroticism using DNA pooling

et al. 2007

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We describe a multistage approach to identify single nucleotide polymorphisms (SNPs) associated with neuroticism, a personality trait that shares genetic determinants with major depression and anxiety disorders. Whole genome association with 452 574 SNPs was performed on DNA pools from B2000 individuals selected on extremes of neuroticism scores from a cohort of 88 142 people from southwest England. The most significant SNPs were then genotyped on independent samples to replicate findings. We were able to replicate association of one SNP within the PDE4D gene in a second sample collected by our laboratory and in a family-based test in an independent sample; however, the SNP was not significantly associated with neuroticism in two other independent samples. We also observed an enrichment of low P-values in known regions of copy number variations. Simulation indicates that our study had B80% power to identify neuroticism loci in the genome with odds ratio (OR) > 2, and B50% power to identify small effects (OR = 1.5). Since we failed to find any loci accounting for more than 1% of the variance, the heritability of neuroticism probably arises from many loci each explaining much less than 1%. Our findings argue the need for much larger samples than anticipated in genetic association studies and that the biological basis of emotional disorders is extremely complex.

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Section: Discussionmentioning

confidence: 99%

A whole genome association study of neuroticism using DNA pooling

et al. 2007

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“…Individuals within the highest and lowest 15% of HDL-C values at the initiation of the trial were chosen for analysis. Clinical and demographic data for genotyped individuals is provided elsewhere (5). The second population was from the TNT trial (17), which included 10,001 individuals with coronary heart disease (CHD) who were followed for five years to determine the effect of atorvastatin on new cardiovascular events.…”

Section: Genetic Analysismentioning

confidence: 99%

“…The importance of HDL-C in disease makes it amenable to candidate-gene and whole-genome association studies (5)(6)(7)(8)(9). Because of the accuracy with which HDL-C can be determined and its high heritability, studies with HDL-C often yield positive results with cholesteryl ester transfer protein (CETP) generally found to be the most highly associated gene.…”

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confidence: 99%

Regulation of apoAI processing by procollagen C-proteinase enhancer-2 and bone morphogenetic protein-1

Zhu

Gardner

Pullinger

et al. 2009

Journal of Lipid Research

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Given the increased prevalence of cardiovascular disease in the world, the search for genetic variations controlling the levels of risk factors associated with the development of the disease continues. Multiple genetic association studies suggest the involvement of procollagen C-proteinase enhancer-2 (PCPE2) in modulating HDL-C levels. Therefore biochemical and mechanistic studies were undertaken to determine whether there might be a basis for a role of PCPE2 in HDL biogenesis. Our studies indicate that PCPE2 accelerates the proteolytic processing of pro-apolipoprotein (apo) AI by enhancing the cleavage of the hexapeptide extension present at the N terminus of apoAI. Surface Plasmon Resonance and immunoprecipitation studies indicate that PCPE2 interacts with BMP-1 and pro-apoAI to form a ternary pro-apoAI/BMP-1/PCPE2 complex. The most favorable interaction among these proteins begins with the association of BMP-1 to pro-apoAI followed by the binding of PCPE2 which further stabilizes the complex. PCPE2 resides, along with apoAI, on the HDL fraction of lipoproteins in human plasma supporting a relationship between HDL and PCPE2. Taken together, the findings from our studies identify a new player in the regulation of apoAI post-translational processing and open a new avenue to the study of mechanisms involved in the regulation of apoAI synthesis, HDL levels, and potentially, cardiovascular disease.-Zhu, J., J. Gardner, C. R. Pullinger, J. P. Kane, J. F. Thompson, and O. L. Francone. Regulation of apoAI processing by procollagen C-proteinase enhancer-2 and bone morphogenetic protein-1. J. Lipid Res. 2009Res. . 50: 1330Res. -1339 Supplementary key words apoAI synthesisDyslipidemia is a major risk factor for premature development of cardiovascular disease. A high ratio of atherogenic lipoproteins (VLDL, LDL, and IDL) to HDL leads to endothelial dysfunction, focal inflammation, and oxidative stress resulting in the initiation and progression of atherosclerosis. Plasma levels of HDL are inversely correlated with the onset of coronary artery disease as attested to by the outcome of several large prospective epidemiological studies (1, 2). The protective effect of HDL is due, at least in part, to the role of this class of lipoproteins in modulating inflammation and mediating cholesterol transport from peripheral cells to sites of reutilization and degradation (3). Apolipoprotein AI (apoAI); the main protein moiety of HDL; drives the formation and speciation of HDL resulting in a very heterogeneous class of particles, particularly with respect to particle size, density, protein content, and surface charge, which determines their functional role and metabolic fate (4). Understanding the processes involved in the synthesis and maturation of HDL species will ultimately provide the knowledge required to understand and appreciate the functional significance of each of the HDL subpopulations and their impact in the development of atherosclerosis.The importance of HDL-C in disease makes it amenable to candidate-gene an...

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“…23 Aiming to reduce experimental costs, DNA-pooling analysis has gained interest as a potential alternative to individual genotyping. [24][25] So far risk factors for a number of complex traits such as alcohol addiction, 26 mental impairment, [27][28] multiple sclerosis 29 and abnormal cholesterol levels 30 have been identified. Furthermore, these studies have been greatly facilitated by development of specialized analysis software such as GenePool 31 and additions such as GPFrontend and GPGraphics (Uebe et al, submitted) focused on interpretation and graphical evaluation of the pooled hybridization intensities at the single-array SNP.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide association study with DNA pooling identifies variants at CNTNAP2 associated with pseudoexfoliation syndrome

et al. 2010

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Genetic and nongenetic factors contribute to development of pseudoexfoliation (PEX) syndrome, a complex, age-related, generalized matrix process frequently associated with glaucoma. To identify specific genetic variants underlying its etiology, we performed a genome-wide association study (GWAS) using a DNA-pooling approach. Therefore, equimolar amounts of DNA samples of 80 subjects with PEX syndrome, 80 with PEX glaucoma (PEXG) and 80 controls were combined into separate pools and hybridized to 500K SNP arrays (Affymetrix). Array probe intensity data were analyzed and visualized with expressly developed software tools GPFrontend and GPGraphics in combination with GenePool software. For replication, independent German cohorts of 610 unrelated patients with PEX/PEXG and 364 controls as well as Italian cohorts of 249 patients and 190 controls were used. Of 19, 17 SNPs showing significant allele frequency difference in DNA pools were confirmed by individual genotyping. Further single genotyping at CNTNAP2 locus revealed association between PEX/PEXG for two SNPs, which was confirmed in an independent German but not the Italian cohort. Both SNPs remained significant in the combined German cohorts even after Bonferroni correction (rs2107856: P c ¼0.0108, rs2141388: P c ¼0.0072). CNTNAP2 was found to be ubiquitously expressed in all human ocular tissues, particularly in retina, and localized to cell membranes of epithelial, endothelial, smooth muscle, glial and neuronal cells. Confirming efficiency of GWAS with DNA-pooling approach by detection of the known LOXL1 locus, our study data show evidence for association of CNTNAP2 with PEX syndrome and PEXG in German patients.

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Application of pooled genotyping to scan candidate regions for association with HDL cholesterol levels

Cited by 87 publications

References 28 publications

A whole genome association study of neuroticism using DNA pooling

A whole genome association study of neuroticism using DNA pooling

Regulation of apoAI processing by procollagen C-proteinase enhancer-2 and bone morphogenetic protein-1

Genome-wide association study with DNA pooling identifies variants at CNTNAP2 associated with pseudoexfoliation syndrome

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