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

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. Electronic supplementary material The online version of this article (doi:10.1186/s13073-015-0211-x) contains supplementary material, which is available to authorized users

Additional file 1: Table S1. of Concept and design of a genome-wide association genotyping array tailored for transplantation-specific studies

Tagging and coverage of MHC region markers. Table S2: Tagging and coverage of Tx-specific genes. Table S3: Untranslated regions (UTRs) considered in the TxArray design. Table S4: Loss-of-function variants included in the TxArray. Table S5: Copy number polymorphisms (CNPs) and variations (CNVs) included in the TxArray. (DOCX 54 kb