Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Li YR

PROVIDER: S-EPMC4589899 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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

Li Yun R YR van Setten Jessica J Verma Shefali S SS Lu Yontao Y Holmes Michael V MV Gao Hui H Lek Monkol M Nair Nikhil N Chandrupatla Hareesh H Chang Baoli B Karczewski Konrad J KJ Karczewski Konrad J KJ Wong Chanel C Mohebnasab Maede M Mukhtar Eyas E Phillips Randy R Tragante Vinicius V Hou Cuiping C Steel Laura L Lee Takesha T Garifallou James J Guettouche Toumy T Cao Hongzhi H Guan Weihua W Himes Aubree A van Houten Jacob J Pasquier Andrew A Yu Reina R Carrigan Elena E Miller Michael B MB Schladt David D Akdere Abdullah A Gonzalez Ana A Llyod Kelsey M KM McGinn Daniel D Gangasani Abhinav A Michaud Zach Z Colasacco Abigail A Snyder James J Thomas Kelly K Wang Tiancheng T Wu Baolin B Alzahrani Alhusain J AJ Al-Ali Amein K AK Al-Muhanna Fahad A FA Al-Rubaish Abdullah M AM Al-Mueilo Samir S Monos Dimitri S DS Murphy Barbara B Olthoff Kim M KM Wijmenga Cisca C Webster Teresa T Kamoun Malek M Balasubramanian Suganthi S Lanktree Matthew B MB Oetting William S WS Garcia-Pavia Pablo P MacArthur Daniel G DG de Bakker Paul I W PI Hakonarson Hakon H Birdwell Kelly A KA Jacobson Pamala A PA Ritchie Marylyn D MD Asselbergs Folkert W FW Israni Ajay K AK Shaked Abraham A Keating Brendan J BJ

Genome medicine 20151001

<h4>Background</h4>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 l ...[more]

PMID: 26423053

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Project description:Background In cattle, genome-wide association studies (GWAS) have largely focused on European or Asian breeds, using genotyping arrays that were primarily designed for European cattle. Because there is growing interest in performing GWAS in African breeds, we have assessed the performance of 23 commercial bovine genotyping arrays for capturing the diversity across African breeds and performing imputation. We used 409 whole-genome sequences (WGS) spanning global cattle breeds, and a real cohort of 2481 individuals (including African breeds) that were genotyped with the Illumina high-density (HD) array and the GeneSeek bovine 50 k array. Results We found that commercially available arrays were not effective in capturing variants that segregate among African indicine animals. Only 6% of these variants in high linkage disequilibrium (LD) (r2 > 0.8) were on the best performing arrays, which contrasts with the 17% and 25% in African and European taurine cattle, respectively. However, imputation from available HD arrays can successfully capture most variants (accuracies up to 0.93), mainly when using a global, not continent-specific, reference panel, which partially reflects the unusually high levels of admixture on the continent. When considering functional variants, the GGPF250 array performed best for tagging WGS variants and imputation. Finally, we show that imputation from low-density arrays can perform almost as well as HD arrays, if a two-stage imputation approach is adopted, i.e. first imputing to HD and then to WGS, which can potentially reduce the costs of GWAS. Conclusions Our results show that the choice of an array should be based on a balance between the objective of the study and the breed/population considered, with the HD and BOS1 arrays being the best choice for both taurine and indicine breeds when performing GWAS, and the GGPF250 being preferable for fine-mapping studies. Moreover, our results suggest that there is no advantage to using the indicus-specific arrays for indicus breeds, regardless of the objective. Finally, we show that using a reference panel that better represents global bovine diversity improves imputation accuracy, particularly for non-European taurine populations. Supplementary Information The online version contains supplementary material available at 10.1186/s12711-022-00751-5.

Dataset Information

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

Publications

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

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