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Concept and design of a genome-wide association genotyping array tailored for transplantation-specific studies.

Li YR, van Setten J, Verma SS, Lu Y, Holmes MV, Gao H, Lek M, Nair N, Chandrupatla H, Chang B, Karczewski KJ, Wong C, Mohebnasab M, Mukhtar E, Phillips R, Tragante V, Hou C, Steel L, Lee T, Garifallou J, Guettouche T, Cao H, Guan W, Himes A, van Houten J, Pasquier A, Yu R, Carrigan E, Miller MB, Schladt D, Akdere A, Gonzalez A, Llyod KM, McGinn D, Gangasani A, Michaud Z, Colasacco A, Snyder J, Thomas K, Wang T, Wu B, Alzahrani AJ, Al-Ali AK, Al-Muhanna FA, Al-Rubaish AM, Al-Mueilo S, Monos DS, Murphy B, Olthoff KM, Wijmenga C, Webster T, Kamoun M, Balasubramanian S, Lanktree MB, Oetting WS, Garcia-Pavia P, MacArthur DG, de Bakker PI, Hakonarson H, Birdwell KA, Jacobson PA, Ritchie MD, Asselbergs FW, Israni AK, Shaked A, Keating BJ - Genome Med (2015)

Bottom Line: We demonstrate much higher capture of the natural killer cell immunoglobulin-like receptor (KIR) region versus comparable platforms.Overall, we show that the genotyping quality and coverage of the TxArray is very high when compared to reference samples and to other genome-wide genotyping platforms.We have designed a comprehensive genome-wide genotyping tool which enables accurate association testing and imputation of ungenotyped SNPs, facilitating powerful and cost-effective large-scale genotyping of transplant-related studies.

View Article: PubMed Central - PubMed

Affiliation: Medical Scientist Training Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

ABSTRACT

Background: In addition to HLA genetic incompatibility, non-HLA difference between donor and recipients of transplantation leading to allograft rejection are now becoming evident. We aimed to create a unique genome-wide platform to facilitate genomic research studies in transplant-related studies. We designed a genome-wide genotyping tool based on the most recent human genomic reference datasets, and included customization for known and potentially relevant metabolic and pharmacological loci relevant to transplantation.

Methods: We describe here the design and implementation of a customized genome-wide genotyping array, the 'TxArray', comprising approximately 782,000 markers with tailored content for deeper capture of variants across HLA, KIR, pharmacogenomic, and metabolic loci important in transplantation. To test concordance and genotyping quality, we genotyped 85 HapMap samples on the array, including eight trios.

Results: We show low Mendelian error rates and high concordance rates for HapMap samples (average parent-parent-child heritability of 0.997, and concordance of 0.996). We performed genotype imputation across autosomal regions, masking directly genotyped SNPs to assess imputation accuracy and report an accuracy of >0.962 for directly genotyped SNPs. We demonstrate much higher capture of the natural killer cell immunoglobulin-like receptor (KIR) region versus comparable platforms. Overall, we show that the genotyping quality and coverage of the TxArray is very high when compared to reference samples and to other genome-wide genotyping platforms.

Conclusions: We have designed a comprehensive genome-wide genotyping tool which enables accurate association testing and imputation of ungenotyped SNPs, facilitating powerful and cost-effective large-scale genotyping of transplant-related studies.

No MeSH data available.


Comparison of coverage of 1000 genomes project reference panel between TxArray and other genome-wide genotyping platforms for variants with MAF >0.05 (a) and >0.01 (b). Coverage (ordinate) for the 1000 Genomes Project Phase I integrated reference panel was assessed using maximum r2 (abscissa), at an MAF cutoff of 0.05 (a) and 0.01 (b). Populations included: (1) African ancestry (AAM): Yoruba in Ibadan, Nigeria (YRI) and Americans of African Ancestry in SouthWest, USA (ASW); (2) Admixed American (AMR): Colombians from Medellin, Colombia (CLM), Mexican Ancestry from Los Angeles USA (MXL), and Puerto Ricans from Puerto Rico (PUR); (3) Asian (ASN): Han Chinese in Beijing (CHB), Southern Han Chinese (CHS), Japanese in Tokyo, Japan (JPT); and (4) European ancestry (CTI): Utah residents with ancestry from Northern Western Europe (CTU), Central and Eastern European (CEU), and Toscani in Italia (TSI), as described in the HapMap and 1KGP. The platforms compared include the TxArray using 767,203 SNPs passing QC. ILMN_1M and ILMN660 refer to Illumina’s Infinium one million and the Illumina 660K genotyping platforms. Affy_6.0 refers to the Affymetrix 6.0 SNP chip containing approximately 906,600 SNPs
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Fig3: Comparison of coverage of 1000 genomes project reference panel between TxArray and other genome-wide genotyping platforms for variants with MAF >0.05 (a) and >0.01 (b). Coverage (ordinate) for the 1000 Genomes Project Phase I integrated reference panel was assessed using maximum r2 (abscissa), at an MAF cutoff of 0.05 (a) and 0.01 (b). Populations included: (1) African ancestry (AAM): Yoruba in Ibadan, Nigeria (YRI) and Americans of African Ancestry in SouthWest, USA (ASW); (2) Admixed American (AMR): Colombians from Medellin, Colombia (CLM), Mexican Ancestry from Los Angeles USA (MXL), and Puerto Ricans from Puerto Rico (PUR); (3) Asian (ASN): Han Chinese in Beijing (CHB), Southern Han Chinese (CHS), Japanese in Tokyo, Japan (JPT); and (4) European ancestry (CTI): Utah residents with ancestry from Northern Western Europe (CTU), Central and Eastern European (CEU), and Toscani in Italia (TSI), as described in the HapMap and 1KGP. The platforms compared include the TxArray using 767,203 SNPs passing QC. ILMN_1M and ILMN660 refer to Illumina’s Infinium one million and the Illumina 660K genotyping platforms. Affy_6.0 refers to the Affymetrix 6.0 SNP chip containing approximately 906,600 SNPs

Mentions: Figure 3a and b shows the composite coverage of markers in the 1KGP panel by the markers genotyped on the TxArray versus other conventional GWAS products for European (CEU and Toscani in Italia (TSI)), African (ASW/YRI), Admixed American (AMR) (Colombians from Medellin, Colombia (CLM), Mexican Ancestry from Los Angeles USA (MXL), and Puerto Ricans from Puerto Rico (PUR)), and Asian (ASN) (CHB, Southern Han Chinese (CHS), and JPT) individuals using MAF cutoffs of >0.01 and >0.05 for the full range of r2 cutoff thresholds (from r2 = 0 to 1). The TxArray performed comparably next to these other genotyping SNP chips, which were designed to provide optimal genome-wide coverage even though the TxArray devoted a significant number of markers to transplant-specific, rare loss of function and MHC/KIR specific content.Fig. 3


Concept and design of a genome-wide association genotyping array tailored for transplantation-specific studies.

Li YR, van Setten J, Verma SS, Lu Y, Holmes MV, Gao H, Lek M, Nair N, Chandrupatla H, Chang B, Karczewski KJ, Wong C, Mohebnasab M, Mukhtar E, Phillips R, Tragante V, Hou C, Steel L, Lee T, Garifallou J, Guettouche T, Cao H, Guan W, Himes A, van Houten J, Pasquier A, Yu R, Carrigan E, Miller MB, Schladt D, Akdere A, Gonzalez A, Llyod KM, McGinn D, Gangasani A, Michaud Z, Colasacco A, Snyder J, Thomas K, Wang T, Wu B, Alzahrani AJ, Al-Ali AK, Al-Muhanna FA, Al-Rubaish AM, Al-Mueilo S, Monos DS, Murphy B, Olthoff KM, Wijmenga C, Webster T, Kamoun M, Balasubramanian S, Lanktree MB, Oetting WS, Garcia-Pavia P, MacArthur DG, de Bakker PI, Hakonarson H, Birdwell KA, Jacobson PA, Ritchie MD, Asselbergs FW, Israni AK, Shaked A, Keating BJ - Genome Med (2015)

Comparison of coverage of 1000 genomes project reference panel between TxArray and other genome-wide genotyping platforms for variants with MAF >0.05 (a) and >0.01 (b). Coverage (ordinate) for the 1000 Genomes Project Phase I integrated reference panel was assessed using maximum r2 (abscissa), at an MAF cutoff of 0.05 (a) and 0.01 (b). Populations included: (1) African ancestry (AAM): Yoruba in Ibadan, Nigeria (YRI) and Americans of African Ancestry in SouthWest, USA (ASW); (2) Admixed American (AMR): Colombians from Medellin, Colombia (CLM), Mexican Ancestry from Los Angeles USA (MXL), and Puerto Ricans from Puerto Rico (PUR); (3) Asian (ASN): Han Chinese in Beijing (CHB), Southern Han Chinese (CHS), Japanese in Tokyo, Japan (JPT); and (4) European ancestry (CTI): Utah residents with ancestry from Northern Western Europe (CTU), Central and Eastern European (CEU), and Toscani in Italia (TSI), as described in the HapMap and 1KGP. The platforms compared include the TxArray using 767,203 SNPs passing QC. ILMN_1M and ILMN660 refer to Illumina’s Infinium one million and the Illumina 660K genotyping platforms. Affy_6.0 refers to the Affymetrix 6.0 SNP chip containing approximately 906,600 SNPs
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4589899&req=5

Fig3: Comparison of coverage of 1000 genomes project reference panel between TxArray and other genome-wide genotyping platforms for variants with MAF >0.05 (a) and >0.01 (b). Coverage (ordinate) for the 1000 Genomes Project Phase I integrated reference panel was assessed using maximum r2 (abscissa), at an MAF cutoff of 0.05 (a) and 0.01 (b). Populations included: (1) African ancestry (AAM): Yoruba in Ibadan, Nigeria (YRI) and Americans of African Ancestry in SouthWest, USA (ASW); (2) Admixed American (AMR): Colombians from Medellin, Colombia (CLM), Mexican Ancestry from Los Angeles USA (MXL), and Puerto Ricans from Puerto Rico (PUR); (3) Asian (ASN): Han Chinese in Beijing (CHB), Southern Han Chinese (CHS), Japanese in Tokyo, Japan (JPT); and (4) European ancestry (CTI): Utah residents with ancestry from Northern Western Europe (CTU), Central and Eastern European (CEU), and Toscani in Italia (TSI), as described in the HapMap and 1KGP. The platforms compared include the TxArray using 767,203 SNPs passing QC. ILMN_1M and ILMN660 refer to Illumina’s Infinium one million and the Illumina 660K genotyping platforms. Affy_6.0 refers to the Affymetrix 6.0 SNP chip containing approximately 906,600 SNPs
Mentions: Figure 3a and b shows the composite coverage of markers in the 1KGP panel by the markers genotyped on the TxArray versus other conventional GWAS products for European (CEU and Toscani in Italia (TSI)), African (ASW/YRI), Admixed American (AMR) (Colombians from Medellin, Colombia (CLM), Mexican Ancestry from Los Angeles USA (MXL), and Puerto Ricans from Puerto Rico (PUR)), and Asian (ASN) (CHB, Southern Han Chinese (CHS), and JPT) individuals using MAF cutoffs of >0.01 and >0.05 for the full range of r2 cutoff thresholds (from r2 = 0 to 1). The TxArray performed comparably next to these other genotyping SNP chips, which were designed to provide optimal genome-wide coverage even though the TxArray devoted a significant number of markers to transplant-specific, rare loss of function and MHC/KIR specific content.Fig. 3

Bottom Line: We demonstrate much higher capture of the natural killer cell immunoglobulin-like receptor (KIR) region versus comparable platforms.Overall, we show that the genotyping quality and coverage of the TxArray is very high when compared to reference samples and to other genome-wide genotyping platforms.We have designed a comprehensive genome-wide genotyping tool which enables accurate association testing and imputation of ungenotyped SNPs, facilitating powerful and cost-effective large-scale genotyping of transplant-related studies.

View Article: PubMed Central - PubMed

Affiliation: Medical Scientist Training Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

ABSTRACT

Background: In addition to HLA genetic incompatibility, non-HLA difference between donor and recipients of transplantation leading to allograft rejection are now becoming evident. We aimed to create a unique genome-wide platform to facilitate genomic research studies in transplant-related studies. We designed a genome-wide genotyping tool based on the most recent human genomic reference datasets, and included customization for known and potentially relevant metabolic and pharmacological loci relevant to transplantation.

Methods: We describe here the design and implementation of a customized genome-wide genotyping array, the 'TxArray', comprising approximately 782,000 markers with tailored content for deeper capture of variants across HLA, KIR, pharmacogenomic, and metabolic loci important in transplantation. To test concordance and genotyping quality, we genotyped 85 HapMap samples on the array, including eight trios.

Results: We show low Mendelian error rates and high concordance rates for HapMap samples (average parent-parent-child heritability of 0.997, and concordance of 0.996). We performed genotype imputation across autosomal regions, masking directly genotyped SNPs to assess imputation accuracy and report an accuracy of >0.962 for directly genotyped SNPs. We demonstrate much higher capture of the natural killer cell immunoglobulin-like receptor (KIR) region versus comparable platforms. Overall, we show that the genotyping quality and coverage of the TxArray is very high when compared to reference samples and to other genome-wide genotyping platforms.

Conclusions: We have designed a comprehensive genome-wide genotyping tool which enables accurate association testing and imputation of ungenotyped SNPs, facilitating powerful and cost-effective large-scale genotyping of transplant-related studies.

No MeSH data available.