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Genome Med. 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.

Author information

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.

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.

PMID:
26423053
PMCID:
PMC4589899
DOI:
10.1186/s13073-015-0211-x
[Indexed for MEDLINE]
Free PMC Article

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