Li Yun R, van Setten Jessica, Verma Shefali S, Lu Yontao, Holmes Michael V, Gao Hui, Lek Monkol, Nair Nikhil, Chandrupatla Hareesh, Chang Baoli, Karczewski Konrad J, Wong Chanel, Mohebnasab Maede, Mukhtar Eyas, Phillips Randy, Tragante Vinicius, Hou Cuiping, Steel Laura, Lee Takesha, Garifallou James, Guettouche Toumy, Cao Hongzhi, Guan Weihua, Himes Aubree, van Houten Jacob, Pasquier Andrew, Yu Reina, Carrigan Elena, Miller Michael B, Schladt David, Akdere Abdullah, Gonzalez Ana, Llyod Kelsey M, McGinn Daniel, Gangasani Abhinav, Michaud Zach, Colasacco Abigail, Snyder James, Thomas Kelly, Wang Tiancheng, Wu Baolin, Alzahrani Alhusain J, Al-Ali Amein K, Al-Muhanna Fahad A, Al-Rubaish Abdullah M, Al-Mueilo Samir, Monos Dimitri S, Murphy Barbara, Olthoff Kim M, Wijmenga Cisca, Webster Teresa, Kamoun Malek, Balasubramanian Suganthi, Lanktree Matthew B, Oetting William S, Garcia-Pavia Pablo, MacArthur Daniel G, de Bakker Paul I W, Hakonarson Hakon, Birdwell Kelly A, Jacobson Pamala A, Ritchie Marylyn D, Asselbergs Folkert W, Israni Ajay K, Shaked Abraham, Keating Brendan J
Medical Scientist Training Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Genome Med. 2015 Oct 1;7:90. doi: 10.1186/s13073-015-0211-x.
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.
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.
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.
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.
除了HLA基因不相容性外，移植供体和受体之间导致同种异体移植排斥的非HLA差异现在也日益明显。我们旨在创建一个独特的全基因组平台，以促进移植相关研究中的基因组学研究。我们基于最新的人类基因组参考数据集设计了一种全基因组基因分型工具，并针对与移植相关的已知和潜在相关代谢及药理基因座进行了定制。
我们在此描述一种定制的全基因组基因分型阵列“TxArray”的设计与实施，该阵列包含约782,000个标记，其内容经过定制，以便更深入地捕获在移植中重要的HLA、KIR、药物基因组学和代谢基因座上的变异。为了测试一致性和基因分型质量，我们在该阵列上对85个HapMap样本进行了基因分型，包括8个三联体。
我们显示HapMap样本的孟德尔错误率低且一致性率高（平均亲子遗传率为0.997，一致性为0.996）。我们在常染色体区域进行了基因型填充，掩盖直接基因分型的单核苷酸多态性（SNP）以评估填充准确性，并报告直接基因分型SNP的准确性>0.962。与可比平台相比，我们证明对自然杀伤细胞免疫球蛋白样受体（KIR）区域的捕获率要高得多。总体而言，与参考样本和其他全基因组基因分型平台相比，我们表明TxArray的基因分型质量和覆盖范围非常高。
我们设计了一种全面的全基因组基因分型工具，该工具能够进行准确的关联测试和对未基因分型SNP的填充，有助于进行强大且具有成本效益的移植相关研究的大规模基因分型。
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