Concept and design of a genome-wide association genotyping array tailored for transplantation-specific studies.
Concept and design of a genome-wide association genotyping array tailored for transplantation-specific studies.
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DOI：
10.1186/s13073-015-0211-x
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发表时间：
2015-10-01
期刊：
影响因子：
12.3
通讯作者：
Keating BJ
中科院分区：
文献类型：
--
作者：
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
除了人类白细胞抗原的遗传不相容外，移植供者和受者之间的非人类白细胞抗原差异导致同种异体移植排斥反应也变得越来越明显。我们的目标是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研究。我们设计了一个基于最新的人类基因组参考数据集的全基因组基因分型工具，并包括定制与移植相关的已知和潜在相关的代谢和药理学基因座。我们在这里描述了一个定制的全基因组基因分型阵列的设计和实施，该阵列由大约782,000个标记组成，具有定制的内容，用于更深入地捕获在移植中重要的人类白细胞抗原、KIR、药物基因组和代谢基因座的变异。为了测试一致性和基因分型质量，我们对阵列上的85个HapMap样本进行了基因分型，其中包括8个Trio。我们显示了HapMap样本的低孟德尔错误率和高符合率(平均父母-父母-孩子遗传率为0.997，一致性为0.996)。我们在常染色体区域进行了基因定位，掩盖了直接分型的SNPs，以评估定位的准确性，并报告了直接分型的SNPs的准确率为>；0.962。我们展示了比可比平台更高的自然杀伤细胞免疫球蛋白样受体(KIR)区域的捕获。总体而言，我们表明，与参考样本和其他全基因组基因分型平台相比，Tx阵列的基因分型质量和覆盖率非常高。我们设计了一种全面的全基因组基因分型工具，可以对未分型的SNPs进行准确的关联测试和归类，从而促进功能强大、成本效益高的大规模移植相关研究的基因分型。本文的在线版本(doi：10.1186/s13073-0150211-x)包含补充材料，授权用户可以使用。
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. The online version of this article (doi:10.1186/s13073-015-0211-x) contains supplementary material, which is available to authorized users.