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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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Related in: MedlinePlus

Combined coverage of IBCv1 with the 500 K and one million SNP products for Group1 loci in HapMap populations.For the combined coverage of IBCv1 with the 500 K SNP products (A–F): coverage (y axis) was assessed using Max r2 (× axis), at an MAF cutoff of 0.02, for the HapMap 22 release 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). For combined coverage with the one million SNP products (G–L): Coverage (y axis) was also assessed using Max r2 (× axis), at an MAF cutoff of 0.02, for the HapMap 22 release in CEPH (CEU) (G), Chinese (CHB) plus Japanese (JPT) (H), and Yoruba (YRI) HapMap individuals (I) and coverage with an MAF cutoff of 0.05 in CEU (J), CHB+JPT (K), and YRI individuals (L). IBCv1 refers here to the version1 ITMAT-Broad-CARe array using 45,237 SNPs that passed manufacturers criteria. Affy_5.0 refers to the Affymetrix 5.0 array and ILMN_HapMap550 refers to the Infinium 550 K HumanHap array which contains 500,568 and 555,352 SNPs respectively. Affy_6.0 refers to the Affymetrix 6.0 array and ILMN_1M refers to the Illumina Infinium one million SNP array containing ∼906,600 and ∼1,050,000 SNPs respectively.
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pone-0003583-g005: Combined coverage of IBCv1 with the 500 K and one million SNP products for Group1 loci in HapMap populations.For the combined coverage of IBCv1 with the 500 K SNP products (A–F): coverage (y axis) was assessed using Max r2 (× axis), at an MAF cutoff of 0.02, for the HapMap 22 release 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). For combined coverage with the one million SNP products (G–L): Coverage (y axis) was also assessed using Max r2 (× axis), at an MAF cutoff of 0.02, for the HapMap 22 release in CEPH (CEU) (G), Chinese (CHB) plus Japanese (JPT) (H), and Yoruba (YRI) HapMap individuals (I) and coverage with an MAF cutoff of 0.05 in CEU (J), CHB+JPT (K), and YRI individuals (L). IBCv1 refers here to the version1 ITMAT-Broad-CARe array using 45,237 SNPs that passed manufacturers criteria. Affy_5.0 refers to the Affymetrix 5.0 array and ILMN_HapMap550 refers to the Infinium 550 K HumanHap array which contains 500,568 and 555,352 SNPs respectively. Affy_6.0 refers to the Affymetrix 6.0 array and ILMN_1M refers to the Illumina Infinium one million SNP array containing ∼906,600 and ∼1,050,000 SNPs respectively.

Mentions: The combined coverage of IBCv1 with a number of the GWAS products was assessed for Group 1 loci. The coverage of the IBCv1 alone, with both of the 500 K SNP GWAS and with the one million SNP array products across the Group 1 loci is illustrated in Figure 5 under varying MAF thresholds across the HapMap populations. The combined coverage using IBCv1 with both 1 M SNP products is similar for Caucasians and Asian HapMap samples. The increase in coverage is more pronounced in African HapMap samples, reflecting the dense marker tagging for YRI in the IBC array.


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)

Combined coverage of IBCv1 with the 500 K and one million SNP products for Group1 loci in HapMap populations.For the combined coverage of IBCv1 with the 500 K SNP products (A–F): coverage (y axis) was assessed using Max r2 (× axis), at an MAF cutoff of 0.02, for the HapMap 22 release 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). For combined coverage with the one million SNP products (G–L): Coverage (y axis) was also assessed using Max r2 (× axis), at an MAF cutoff of 0.02, for the HapMap 22 release in CEPH (CEU) (G), Chinese (CHB) plus Japanese (JPT) (H), and Yoruba (YRI) HapMap individuals (I) and coverage with an MAF cutoff of 0.05 in CEU (J), CHB+JPT (K), and YRI individuals (L). IBCv1 refers here to the version1 ITMAT-Broad-CARe array using 45,237 SNPs that passed manufacturers criteria. Affy_5.0 refers to the Affymetrix 5.0 array and ILMN_HapMap550 refers to the Infinium 550 K HumanHap array which contains 500,568 and 555,352 SNPs respectively. Affy_6.0 refers to the Affymetrix 6.0 array and ILMN_1M refers to the Illumina Infinium one million SNP array containing ∼906,600 and ∼1,050,000 SNPs respectively.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0003583-g005: Combined coverage of IBCv1 with the 500 K and one million SNP products for Group1 loci in HapMap populations.For the combined coverage of IBCv1 with the 500 K SNP products (A–F): coverage (y axis) was assessed using Max r2 (× axis), at an MAF cutoff of 0.02, for the HapMap 22 release 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). For combined coverage with the one million SNP products (G–L): Coverage (y axis) was also assessed using Max r2 (× axis), at an MAF cutoff of 0.02, for the HapMap 22 release in CEPH (CEU) (G), Chinese (CHB) plus Japanese (JPT) (H), and Yoruba (YRI) HapMap individuals (I) and coverage with an MAF cutoff of 0.05 in CEU (J), CHB+JPT (K), and YRI individuals (L). IBCv1 refers here to the version1 ITMAT-Broad-CARe array using 45,237 SNPs that passed manufacturers criteria. Affy_5.0 refers to the Affymetrix 5.0 array and ILMN_HapMap550 refers to the Infinium 550 K HumanHap array which contains 500,568 and 555,352 SNPs respectively. Affy_6.0 refers to the Affymetrix 6.0 array and ILMN_1M refers to the Illumina Infinium one million SNP array containing ∼906,600 and ∼1,050,000 SNPs respectively.
Mentions: The combined coverage of IBCv1 with a number of the GWAS products was assessed for Group 1 loci. The coverage of the IBCv1 alone, with both of the 500 K SNP GWAS and with the one million SNP array products across the Group 1 loci is illustrated in Figure 5 under varying MAF thresholds across the HapMap populations. The combined coverage using IBCv1 with both 1 M SNP products is similar for Caucasians and Asian HapMap samples. The increase in coverage is more pronounced in African HapMap samples, reflecting the dense marker tagging for YRI in the IBC array.

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