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Concept, design and implementation of a cardiovascular gene-centric 50 k SNP array for large-scale genomic association studies.

Keating BJ, Tischfield S, Murray SS, Bhangale T, Price TS, Glessner JT, Galver L, Barrett JC, Grant SF, Farlow DN, Chandrupatla HR, Hansen M, Ajmal S, Papanicolaou GJ, Guo Y, Li M, Derohannessian S, de Bakker PI, Bailey SD, Montpetit A, Edmondson AC, Taylor K, Gai X, Wang SS, Fornage M, Shaikh T, Groop L, Boehnke M, Hall AS, Hattersley AT, Frackelton E, Patterson N, Chiang CW, Kim CE, Fabsitz RR, Ouwehand W, Price AL, Munroe P, Caulfield M, Drake T, Boerwinkle E, Reich D, Whitehead AS, Cappola TP, Samani NJ, Lusis AJ, Schadt E, Wilson JG, Koenig W, McCarthy MI, Kathiresan S, Gabriel SB, Hakonarson H, Anand SS, Reilly M, Engert JC, Nickerson DA, Rader DJ, Hirschhorn JN, Fitzgerald GA - PLoS ONE (2008)

Bottom Line: True complex disease-associated loci often exert modest effects, so their delineation currently requires integration of diverse phenotypic data from large studies to ensure robust meta-analyses.The custom flexibility of the array platform facilitated interrogation of loci at differing stringencies, according to a gene prioritization strategy that allows saturation of high priority loci with a greater density of markers than the existing GWAS tools, particularly in African HapMap samples.DNA from over 200,000 extensively phenotyped individuals will be genotyped with this array with a significant portion of the generated data being released into the academic domain facilitating in silico replication attempts, analyses of rare variants and cross-cohort meta-analyses in diverse populations.

View Article: PubMed Central - PubMed

Affiliation: The Institute for Translational Medicine and Therapeutics, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvannia, USA.

ABSTRACT
A wealth of genetic associations for cardiovascular and metabolic phenotypes in humans has been accumulating over the last decade, in particular a large number of loci derived from recent genome wide association studies (GWAS). True complex disease-associated loci often exert modest effects, so their delineation currently requires integration of diverse phenotypic data from large studies to ensure robust meta-analyses. We have designed a gene-centric 50 K single nucleotide polymorphism (SNP) array to assess potentially relevant loci across a range of cardiovascular, metabolic and inflammatory syndromes. The array utilizes a "cosmopolitan" tagging approach to capture the genetic diversity across approximately 2,000 loci in populations represented in the HapMap and SeattleSNPs projects. The array content is informed by GWAS of vascular and inflammatory disease, expression quantitative trait loci implicated in atherosclerosis, pathway based approaches and comprehensive literature searching. The custom flexibility of the array platform facilitated interrogation of loci at differing stringencies, according to a gene prioritization strategy that allows saturation of high priority loci with a greater density of markers than the existing GWAS tools, particularly in African HapMap samples. We also demonstrate that the IBC array can be used to complement GWAS, increasing coverage in high priority CVD-related loci across all major HapMap populations. DNA from over 200,000 extensively phenotyped individuals will be genotyped with this array with a significant portion of the generated data being released into the academic domain facilitating in silico replication attempts, analyses of rare variants and cross-cohort meta-analyses in diverse populations. These datasets will also facilitate more robust secondary analyses, such as explorations with alternative genetic models, epistasis and gene-environment interactions.

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MAF distribution for IBCv1 assays across studies of Caucasians, African Americans and South Asians.Proportion of polymorphic variants (as a % of total) are described on the y-axis with the x-axis illustrating bins of the minor allele frequencies (MAF) for six different studies; Caucasian Study 1 (n = 2094 European); Caucasian Study 2 (n = 2150 European); Caucasian Study 3 (n = 1054 European American); African American Study 1 (n = 254); African American Study 2 (n = 130) and South Asians (n = 385).
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pone-0003583-g002: MAF distribution for IBCv1 assays across studies of Caucasians, African Americans and South Asians.Proportion of polymorphic variants (as a % of total) are described on the y-axis with the x-axis illustrating bins of the minor allele frequencies (MAF) for six different studies; Caucasian Study 1 (n = 2094 European); Caucasian Study 2 (n = 2150 European); Caucasian Study 3 (n = 1054 European American); African American Study 1 (n = 254); African American Study 2 (n = 130) and South Asians (n = 385).

Mentions: MAFs were assessed across the IBCv1 arrays in 6067 DNA samples collated from three studies with five populations of self described ethnicity, screened for cardiovascular traits; Caucasians (n = 4244 European and n = 1054 US Caucasians); African Americans (n = 384); and South Asians (n = 385). Some 1415 assays across the complete dataset were monomorphic. 2705 and 2566 assays were, respectively, monomorphic across self-described Caucasians and African Americans. Figure 2 illustrates the distribution of MAFs in the Caucasian, African American and South Asian populations, respectively. The various bins for MAFs>0.01 were comparable across all populations examined. Significant variability was evident for variants with MAFs<0.005 which is expected, given the frequency of observations, the varying number of individuals in each ethnic group studied and the natural allele frequency differences of such variants across populations.


Concept, design and implementation of a cardiovascular gene-centric 50 k SNP array for large-scale genomic association studies.

Keating BJ, Tischfield S, Murray SS, Bhangale T, Price TS, Glessner JT, Galver L, Barrett JC, Grant SF, Farlow DN, Chandrupatla HR, Hansen M, Ajmal S, Papanicolaou GJ, Guo Y, Li M, Derohannessian S, de Bakker PI, Bailey SD, Montpetit A, Edmondson AC, Taylor K, Gai X, Wang SS, Fornage M, Shaikh T, Groop L, Boehnke M, Hall AS, Hattersley AT, Frackelton E, Patterson N, Chiang CW, Kim CE, Fabsitz RR, Ouwehand W, Price AL, Munroe P, Caulfield M, Drake T, Boerwinkle E, Reich D, Whitehead AS, Cappola TP, Samani NJ, Lusis AJ, Schadt E, Wilson JG, Koenig W, McCarthy MI, Kathiresan S, Gabriel SB, Hakonarson H, Anand SS, Reilly M, Engert JC, Nickerson DA, Rader DJ, Hirschhorn JN, Fitzgerald GA - PLoS ONE (2008)

MAF distribution for IBCv1 assays across studies of Caucasians, African Americans and South Asians.Proportion of polymorphic variants (as a % of total) are described on the y-axis with the x-axis illustrating bins of the minor allele frequencies (MAF) for six different studies; Caucasian Study 1 (n = 2094 European); Caucasian Study 2 (n = 2150 European); Caucasian Study 3 (n = 1054 European American); African American Study 1 (n = 254); African American Study 2 (n = 130) and South Asians (n = 385).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2571995&req=5

pone-0003583-g002: MAF distribution for IBCv1 assays across studies of Caucasians, African Americans and South Asians.Proportion of polymorphic variants (as a % of total) are described on the y-axis with the x-axis illustrating bins of the minor allele frequencies (MAF) for six different studies; Caucasian Study 1 (n = 2094 European); Caucasian Study 2 (n = 2150 European); Caucasian Study 3 (n = 1054 European American); African American Study 1 (n = 254); African American Study 2 (n = 130) and South Asians (n = 385).
Mentions: MAFs were assessed across the IBCv1 arrays in 6067 DNA samples collated from three studies with five populations of self described ethnicity, screened for cardiovascular traits; Caucasians (n = 4244 European and n = 1054 US Caucasians); African Americans (n = 384); and South Asians (n = 385). Some 1415 assays across the complete dataset were monomorphic. 2705 and 2566 assays were, respectively, monomorphic across self-described Caucasians and African Americans. Figure 2 illustrates the distribution of MAFs in the Caucasian, African American and South Asian populations, respectively. The various bins for MAFs>0.01 were comparable across all populations examined. Significant variability was evident for variants with MAFs<0.005 which is expected, given the frequency of observations, the varying number of individuals in each ethnic group studied and the natural allele frequency differences of such variants across populations.

Bottom Line: True complex disease-associated loci often exert modest effects, so their delineation currently requires integration of diverse phenotypic data from large studies to ensure robust meta-analyses.The custom flexibility of the array platform facilitated interrogation of loci at differing stringencies, according to a gene prioritization strategy that allows saturation of high priority loci with a greater density of markers than the existing GWAS tools, particularly in African HapMap samples.DNA from over 200,000 extensively phenotyped individuals will be genotyped with this array with a significant portion of the generated data being released into the academic domain facilitating in silico replication attempts, analyses of rare variants and cross-cohort meta-analyses in diverse populations.

View Article: PubMed Central - PubMed

Affiliation: The Institute for Translational Medicine and Therapeutics, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvannia, USA.

ABSTRACT
A wealth of genetic associations for cardiovascular and metabolic phenotypes in humans has been accumulating over the last decade, in particular a large number of loci derived from recent genome wide association studies (GWAS). True complex disease-associated loci often exert modest effects, so their delineation currently requires integration of diverse phenotypic data from large studies to ensure robust meta-analyses. We have designed a gene-centric 50 K single nucleotide polymorphism (SNP) array to assess potentially relevant loci across a range of cardiovascular, metabolic and inflammatory syndromes. The array utilizes a "cosmopolitan" tagging approach to capture the genetic diversity across approximately 2,000 loci in populations represented in the HapMap and SeattleSNPs projects. The array content is informed by GWAS of vascular and inflammatory disease, expression quantitative trait loci implicated in atherosclerosis, pathway based approaches and comprehensive literature searching. The custom flexibility of the array platform facilitated interrogation of loci at differing stringencies, according to a gene prioritization strategy that allows saturation of high priority loci with a greater density of markers than the existing GWAS tools, particularly in African HapMap samples. We also demonstrate that the IBC array can be used to complement GWAS, increasing coverage in high priority CVD-related loci across all major HapMap populations. DNA from over 200,000 extensively phenotyped individuals will be genotyped with this array with a significant portion of the generated data being released into the academic domain facilitating in silico replication attempts, analyses of rare variants and cross-cohort meta-analyses in diverse populations. These datasets will also facilitate more robust secondary analyses, such as explorations with alternative genetic models, epistasis and gene-environment interactions.

Show MeSH
Related in: MedlinePlus