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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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Coverage of IBCv1 versus GWAS products for Group1 loci in HapMap populations.Cumulative coverage (y axis) of the HapMap 22 release was assessed using Max r2 (× axis), at an MAF cutoff of 0.02, in CEPH (CEU) (A), Chinese (CHB) plus Japanese (JPT), (B) and Yoruba (YRI) HapMap individuals (C). Coverage was also assessed at an MAF cutoff of 0.05 in CEU (D), CHB+JPT (E), and YRI individuals (F). IBCv1 refers here to version1 ITMAT-Broad-CARe array using 45,237 SNPs passed by the manufacture. ILMN_1M, ILMNHap550 and ILMNHap300 refer to Illumina's Human1M, HumanHap550 (555,352 SNPs) and HumanHap300 (317,503 SNPs) products, respectively. Affy_6.0 and Affy_5.0 refers to Affymetrix 6.0 & Affymetrix 5.0 array products containing ∼906,600 SNPs & 500,568 SNPs respectively.
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pone-0003583-g004: Coverage of IBCv1 versus GWAS products for Group1 loci in HapMap populations.Cumulative coverage (y axis) of the HapMap 22 release was assessed using Max r2 (× axis), at an MAF cutoff of 0.02, in CEPH (CEU) (A), Chinese (CHB) plus Japanese (JPT), (B) and Yoruba (YRI) HapMap individuals (C). Coverage was also assessed at an MAF cutoff of 0.05 in CEU (D), CHB+JPT (E), and YRI individuals (F). IBCv1 refers here to version1 ITMAT-Broad-CARe array using 45,237 SNPs passed by the manufacture. ILMN_1M, ILMNHap550 and ILMNHap300 refer to Illumina's Human1M, HumanHap550 (555,352 SNPs) and HumanHap300 (317,503 SNPs) products, respectively. Affy_6.0 and Affy_5.0 refers to Affymetrix 6.0 & Affymetrix 5.0 array products containing ∼906,600 SNPs & 500,568 SNPs respectively.

Mentions: The coverage of HapMap SNPs was evaluated for all Group 1 loci against the various GWAS products in the HapMap individuals. The maximum r2 value was calculated between each HapMap SNP in the region to a SNP in each respective product. Figures 4 (a) through (f) shows the composite coverage of Group 1 loci from IBCv1 versus several GWAS products for CEU, YRI and CHB+JPT HapMap individuals using MAF cutoffs of >0.02 and >0.05 across the spectrum of r2 thresholds. The coverage using CEUs and CHB+JPT is comparable across all products, although the IBCv1 coverage for YRI is greater. A number of the GWAS products and the IBC array are strongly biased for composition of HapMap SNPs and will obviously have skewed coverage when directly compared. Over 20% of IBCv1 Group1 loci SNPs have not been assayed directly in HapMap with the majority of these additional SNPs derived from SeattleSNPs and the literature. Thus, the IBC array is likely to be more representative of broader population allelic architecture.


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)

Coverage of IBCv1 versus GWAS products for Group1 loci in HapMap populations.Cumulative coverage (y axis) of the HapMap 22 release was assessed using Max r2 (× axis), at an MAF cutoff of 0.02, in CEPH (CEU) (A), Chinese (CHB) plus Japanese (JPT), (B) and Yoruba (YRI) HapMap individuals (C). Coverage was also assessed at an MAF cutoff of 0.05 in CEU (D), CHB+JPT (E), and YRI individuals (F). IBCv1 refers here to version1 ITMAT-Broad-CARe array using 45,237 SNPs passed by the manufacture. ILMN_1M, ILMNHap550 and ILMNHap300 refer to Illumina's Human1M, HumanHap550 (555,352 SNPs) and HumanHap300 (317,503 SNPs) products, respectively. Affy_6.0 and Affy_5.0 refers to Affymetrix 6.0 & Affymetrix 5.0 array products containing ∼906,600 SNPs & 500,568 SNPs respectively.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0003583-g004: Coverage of IBCv1 versus GWAS products for Group1 loci in HapMap populations.Cumulative coverage (y axis) of the HapMap 22 release was assessed using Max r2 (× axis), at an MAF cutoff of 0.02, in CEPH (CEU) (A), Chinese (CHB) plus Japanese (JPT), (B) and Yoruba (YRI) HapMap individuals (C). Coverage was also assessed at an MAF cutoff of 0.05 in CEU (D), CHB+JPT (E), and YRI individuals (F). IBCv1 refers here to version1 ITMAT-Broad-CARe array using 45,237 SNPs passed by the manufacture. ILMN_1M, ILMNHap550 and ILMNHap300 refer to Illumina's Human1M, HumanHap550 (555,352 SNPs) and HumanHap300 (317,503 SNPs) products, respectively. Affy_6.0 and Affy_5.0 refers to Affymetrix 6.0 & Affymetrix 5.0 array products containing ∼906,600 SNPs & 500,568 SNPs respectively.
Mentions: The coverage of HapMap SNPs was evaluated for all Group 1 loci against the various GWAS products in the HapMap individuals. The maximum r2 value was calculated between each HapMap SNP in the region to a SNP in each respective product. Figures 4 (a) through (f) shows the composite coverage of Group 1 loci from IBCv1 versus several GWAS products for CEU, YRI and CHB+JPT HapMap individuals using MAF cutoffs of >0.02 and >0.05 across the spectrum of r2 thresholds. The coverage using CEUs and CHB+JPT is comparable across all products, although the IBCv1 coverage for YRI is greater. A number of the GWAS products and the IBC array are strongly biased for composition of HapMap SNPs and will obviously have skewed coverage when directly compared. Over 20% of IBCv1 Group1 loci SNPs have not been assayed directly in HapMap with the majority of these additional SNPs derived from SeattleSNPs and the literature. Thus, the IBC array is likely to be more representative of broader population allelic architecture.

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