. 2015 Oct 1:7:90.

doi: 10.1186/s13073-015-0211-x.

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

Yun R Li^{1

2}, Jessica van Setten³, Shefali S Verma⁴, Yontao Lu⁵, Michael V Holmes⁶, Hui Gao^{2

6}, Monkol Lek^{7

8}, Nikhil Nair^{2

6}, Hareesh Chandrupatla^{2

6}, Baoli Chang^{2

6}, Konrad J Karczewski^{7

8}, Chanel Wong^{2

6}, Maede Mohebnasab², Eyas Mukhtar^{2

6}, Randy Phillips^{2

6}, Vinicius Tragante³, Cuiping Hou², Laura Steel^{2

6}, Takesha Lee^{2

6}, James Garifallou², Toumy Guettouche², Hongzhi Cao^{9

10}, Weihua Guan¹¹, Aubree Himes^{2

6}, Jacob van Houten², Andrew Pasquier², Reina Yu², Elena Carrigan², Michael B Miller¹², David Schladt¹³, Abdullah Akdere¹, Ana Gonzalez¹, Kelsey M Llyod¹, Daniel McGinn¹, Abhinav Gangasani¹, Zach Michaud¹, Abigail Colasacco¹, James Snyder², Kelly Thomas², Tiancheng Wang², Baolin Wu¹¹, Alhusain J Alzahrani¹⁴, Amein K Al-Ali¹⁵, Fahad A Al-Muhanna¹⁵, Abdullah M Al-Rubaish¹⁵, Samir Al-Mueilo¹⁵, Dimitri S Monos^{2

16}, Barbara Murphy¹⁷, Kim M Olthoff⁶, Cisca Wijmenga¹⁸, Teresa Webster⁵, Malek Kamoun¹⁶, Suganthi Balasubramanian¹⁹, Matthew B Lanktree⁶, William S Oetting²⁰, Pablo Garcia-Pavia²¹, Daniel G MacArthur^{7

8}, Paul I W de Bakker²², Hakon Hakonarson², Kelly A Birdwell²³, Pamala A Jacobson²⁴, Marylyn D Ritchie⁴, Folkert W Asselbergs^{3

25

26}, Ajay K Israni²⁷, Abraham Shaked⁶, Brendan J Keating^{28

29

30

31}

Affiliations

¹ Medical Scientist Training Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
² The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
³ Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands.
⁴ Center for Systems Genomics, The Pennsylvania State University, University Park, PA, USA.
⁵ Affymetrix Incorporated, Santa Clara, CA, USA.
⁶ Penn Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
⁷ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
⁸ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
⁹ BGI-Shenzhen, Shenzhen, China.
¹⁰ Department of Biology, University of Copenhagen, Copenhagen, Denmark.
¹¹ Division of Biostatistics, University of Minnesota, Minneapolis, MN, USA.
¹² Department of Psychology, University of Minnesota, Minneapolis, MN, USA.
¹³ Minneapolis Medical Research Foundation, Hennepin County Medical Center, Minneapolis, MN, USA.
¹⁴ Department of Clinical Laboratories Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia.
¹⁵ College of Medicine, University of Dammam, Dammam, Kingdom of Saudi Arabia.
¹⁶ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania and the Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹⁷ Division of Nephrology and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁸ Department of Genetics, The University Medical Center Groningen, Groningen, The Netherlands.
¹⁹ Program in Computational Biology and Bioinformatics, and Molecular Biophysics and Biochemistry Department, Yale University, New Haven, CT, 06520, USA.
²⁰ Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA.
²¹ Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain.
²² Department of Medical Genetics, Center for Molecular Medicine and Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
²³ School of Medicine, Vanderbilt University, Nashville, TN, USA.
²⁴ College of Pharmacy, University of Minnesota, Minneapolis, USA.
²⁵ Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands.
²⁶ Institute of Cardiovascular Science, faculty of Population Health Sciences, University College London, London, UK.
²⁷ Hennepin County Medical Center, University of Minneosta, Minneapolis, MN, USA.
²⁸ The Children's Hospital of Philadelphia, Philadelphia, PA, USA. bkeating@mail.med.upenn.edu.
²⁹ Penn Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, PA, USA. bkeating@mail.med.upenn.edu.
³⁰ Department of Pediatrics, University of Pennsylvania, Philadelphia, PA, USA. bkeating@mail.med.upenn.edu.
³¹ Division of Transplantation, 2 Dulles, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA, 19104, USA. bkeating@mail.med.upenn.edu.

PMID: 26423053
PMCID: PMC4589899
DOI: 10.1186/s13073-015-0211-x

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

Yun R Li et al. Genome Med. 2015.

. 2015 Oct 1:7:90.

doi: 10.1186/s13073-015-0211-x.

Authors

Affiliations

¹ Medical Scientist Training Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
² The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
³ Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands.
⁴ Center for Systems Genomics, The Pennsylvania State University, University Park, PA, USA.
⁵ Affymetrix Incorporated, Santa Clara, CA, USA.
⁶ Penn Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
⁷ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
⁸ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
⁹ BGI-Shenzhen, Shenzhen, China.
¹⁰ Department of Biology, University of Copenhagen, Copenhagen, Denmark.
¹¹ Division of Biostatistics, University of Minnesota, Minneapolis, MN, USA.
¹² Department of Psychology, University of Minnesota, Minneapolis, MN, USA.
¹³ Minneapolis Medical Research Foundation, Hennepin County Medical Center, Minneapolis, MN, USA.
¹⁴ Department of Clinical Laboratories Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia.
¹⁵ College of Medicine, University of Dammam, Dammam, Kingdom of Saudi Arabia.
¹⁶ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania and the Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹⁷ Division of Nephrology and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁸ Department of Genetics, The University Medical Center Groningen, Groningen, The Netherlands.
¹⁹ Program in Computational Biology and Bioinformatics, and Molecular Biophysics and Biochemistry Department, Yale University, New Haven, CT, 06520, USA.
²⁰ Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA.
²¹ Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain.
²² Department of Medical Genetics, Center for Molecular Medicine and Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
²³ School of Medicine, Vanderbilt University, Nashville, TN, USA.
²⁴ College of Pharmacy, University of Minnesota, Minneapolis, USA.
²⁵ Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands.
²⁶ Institute of Cardiovascular Science, faculty of Population Health Sciences, University College London, London, UK.
²⁷ Hennepin County Medical Center, University of Minneosta, Minneapolis, MN, USA.
²⁸ The Children's Hospital of Philadelphia, Philadelphia, PA, USA. bkeating@mail.med.upenn.edu.
²⁹ Penn Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, PA, USA. bkeating@mail.med.upenn.edu.
³⁰ Department of Pediatrics, University of Pennsylvania, Philadelphia, PA, USA. bkeating@mail.med.upenn.edu.
³¹ Division of Transplantation, 2 Dulles, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA, 19104, USA. bkeating@mail.med.upenn.edu.

PMID: 26423053
PMCID: PMC4589899
DOI: 10.1186/s13073-015-0211-x

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.

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Figures

**Fig. 1**
Key content modules included in the TxArray. Marker modules are divided into those in common with the UK Biobank Axiom Array, Axiom Biobank Genotyping Array, and those unique to the TxArray along with module descriptions and counts of unique markers in each category. The goal of preserving the specific markers already covered on the two existing biobank arrays is maximize shared coverage for future cross-study joint and meta-analyses that may utilize these popular state-of-the art genotyping platforms

**Fig. 2**
Modular content in the TxArray targeting the MHC and custom-designed for transplant-focused association studies. a MHC modules included in the TxArray and the total count of markers either directly tiled or tagged. Note that the marker counts are not unique as some modules overlap. A total of 10,820 and 13,428 unique markers across the *MHC* and extended *MHC* are included in the TxArray. b Major categories of transplant-specific markers included in the array. See methods and supplemental tables for details of design and content considerations

**Fig. 3**
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 r ² (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

**Fig. 4**
Comparison of coverage between TxArray and ILMN_1M genotyping platforms across exonic regions, the extended MHC and the KIR-encoding locus. a Coverage (ordinate) for all exonic markers and UTR region markers in the 1000 genomes reference panel was assessed using max r2 (abscissa), at an MAF cutoff of 0.05 (a) and 0.01 (b), in (1) European ancestry ((CEU) and Tuscany in Italia (TSI)); (2) African ancestry (AAM) (Yoruba in Ibadan, Nigeria (YRI)) and Americans of African Ancestry in SouthWest, USA (ASW); (3) Admixed American (AMR) (Colombians from Medellin, Colombia (CLM), Mexican Ancestry from Los Angeles, USA (MXL), and Puerto Ricans from Puerto Rico (PUR)); and (4) Asian (ASN) (Han Chinese in Beijing (CHB), Southern Han Chinese (CHS), Japanese in Tokyo, Japan (JPT)) HapMap and 1KGP individuals. The compared platforms include the TxArray using 767,203 SNPs that passed manufacturing and standard genotyping QC. ILMN_1M refer to Illumina’s Infinium one million SNP GWAS array. b Comparison of coverage across variants within *KIR*-encoding regions using the TxArray (TX) or the Illumina 1M (ILMN_1M) genotyping platforms across the four major HapMap populations (European (CTU): CEU+TSI; AAM: ASW+YRI; AMR: CLM+MXL+PUR; ASN: CHB+CHS+JPT). Coverage is based on mean r² of variants included in the 1000 genomes phase I reference panel with a MAF of >0.01 (top) or >0.05 (bottom). *KIR* genes included: (*KIR2DP1*, *KIR2DL1*, *KIR2DL2*, *KIR2DL3*, *KIR2DL4*, *KIR2DL5A*, *KIR2DL5B*, *KIR2DS1*, *KIR2DS2*, *KIR2DS3*, *KIR2DS4*, *KIR2DS5*, *KIR3DL1*, *KIR3DL2*, *KIR3DL3*, *KIR3DP1*, *KIR3DS1*, *KIR3DX1*). Coverage was compared for either all *KIR* region markers (left) or only those in exonic regions (right). c Comparison of coverage across the extended *MHC* (25,500,000–34,000,000) using either the TxArray (TX) or the Illumina 1M (ILMN_1M) genotyping platforms across the four major HAPMAP populations (CTU: CEU/TSI; AAM: ASW/YRI; AMR: CLM/MXL/PUR; ASN: CHB/CHS/JPT). Coverage rate is calculated based on the mean achieved r² for variants included in the 1000 Genomes Project (1KGP) Phase I reference panel with a MAF of >0.01 (left) or >0.05 (right)

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

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

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