Key Resource and Design Papers for iGeneTRAiN

Design and Implementation of The International Genetics and Translational Research in Transplantation Network (iGeneTRAiN). In press Transplantation
October 1st 2015

This paper describes in detail the iGeneTRAiN initial 22 genetic studies comprising over 28,000 transplant recipients or donors, which have existing genome-wide genotype data (this number has now grown to nearly 30 studies with over 32,000 and it is still growing). The paper, with input from over 120 iGeneTRAiN co-authors, describes the genetic and phenotypic data available in these comprising heart, kidney, liver, and lung transplant studies. It also formally demonstrates the significant statistical power in iGeneTRAiN to detect main effect genetic association signals across these studies for graft survival, acute rejection, new onset of diabetes after transplantation (NODAT), and for delayed graft function.

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Concept and design of a genome-wide association genotyping array tailored for transplantation-specific studies. Yun Rose Li
et al. In press Genome Medicine
October 1st 2015.

This paper describes in detail the ‘Tx GWAS array’ (Axiom, Affymetrix), a unique genome-wide genotyping tool to facilitate genomic research studies in transplant-related studies. The Tx GWAS array containing approximately 782,000 markers is designed using the most recent human genomic reference datasets, and includes customized content for known and potentially relevant metabolic and pharmacological gene regions relevant to transplantation. This paper formally assesses the performance of the Tx GWAS array on benchmarked reference samples from HapMap/1000 Genomes Project (1KGP). It shows low Mendelian error and high concordance rates. It also demonstrates much higher capture of high priority content such as killer cell immunoglobulin-like receptor (KIR) region versus conventional platforms, and shows the very dense content in the MHC/HLA regions. The imputation pipeline is also described. We have now generated an imputation pipeline comprising the 1KGPv3 and The Genome of The Netherlands (Go-NL)v5 using IMPUTE2 and SHAPEIT which allows approximately 88 million sites across the human genome to be inferred (approximately 15 million of which are typically used for conventional GWAS analyses). We have also constructed a loss-of-function (LoF) pipeline based on the imputed data with the directly and imputed genotypes, and with deep characterization of rich expression resources, which allows deep characterization of LoFs across the phased chromosomes.

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Genome-wide association studies (GWAS) published to date
Only three Transplantation GWA studies, shown below, have been published to date, and the numbers of subjects are very modest by standard GWAS efforts. Hopefully the number of studies, and aggregation of total patients within these studies, will increase dramatically over the next 12 months with iGeneTRAiN and other efforts.

A genome-wide association study of recipient genotype and
medium-term kidney allograft function.

O’Brien RP, Phelan PJ, Conroy J, O’Kelly P, Green A, Keogan M, O’Neill D, Jennings S, Traynor C, Casey J, McCormack M, Conroy R, Chubb A, Ennis S, Shields DC, Cavalleri GL, Conlon PJ.
Clinical Transplantation.2013 May-Jun;27(3):379-87. doi: 10.1111/ctr.12093.

Genetics of new-onset diabetes after transplantation.

McCaughan JA, McKnight AJ, Maxwell AP.
Journal of the American Society of Nephrology.2014 May;25(5):1037-49. doi: 10.1681/ASN.2013040383.

Clinical and Genetic Factors Associated with Cutaneous
Squamous Cell Carcinoma in Kidney and Heart Transplant

Sanders ML, Karnes JH, Denny JC, Roden DM, Ikizler TA, Birdwell KA.
Transplantation Direct.2015 May;1(4). doi: 10.1097/TXD.0000000000000521.

Suhre K, Schwartz JE, Sharma VK, Chen Q, Lee JR, Muthukumar T, Dadhania DM, Ding R, Ikle DN, Bridges ND, Williams NM, Kastenmüller G, Karoly ED, Mohney RP, Abecassis M, Friedewald J, Knechtle SJ, Becker YT, Samstein B, Shaked A, Gross SS, Suthanthiran M.
Journal of the American Society of Nephrology.2015 Jun 5. pii: ASN.2015010107.

Dosing equation for tacrolimus using genetic variants and
clinical factors.

Passey C, Birnbaum AK, Brundage RC, Oetting WS, Israni AK, Jacobson PA.
British Journal of Clinical Pharmacology.2011 Dec;72(6):948-57. doi: 10.1111/j.1365-2125.2011.04039.x.

Circulating cell-free DNA enables noninvasive diagnosis of
heart transplant rejection.

De Vlaminck I, Valantine HA, Snyder TM, Strehl C, Cohen G, Luikart H, Neff NF, Okamoto J, Bernstein D, Weisshaar D, Quake SR, Khush KK.
Sci Transl Med. 2014 Jun 18;6(241):241ra77. doi: 10.1126/scitranslmed.3007803.

Li L, Khush K, Hsieh SC, Ying L, Luikart H, Sigdel T, Roedder S, Yang A, Valantine H, Sarwal MM.
PLoS One. 2013 Dec 16;8(12):e82153. doi: 10.1371/journal.pone.0082153. eCollection 2013.

Temporal response of the human virome to
immunosuppression and antiviral therapy.

De Vlaminck I, Khush KK, Strehl C, Kohli B, Luikart H, Neff NF, Okamoto J, Snyder TM, Cornfield DN, Nicolls MR, Weill D, Bernstein D, Valantine HA, Quake SR.
Cell. 2013 Nov 21;155(5):1178-87. doi: 10.1016/j.cell.2013.10.034.

Recent Transplantation Genomic Reviews/Commentaries

Transplantation genetics: current status and prospects.

B Almoguera, A Shaked, BJ Keating.
American Journal of Transplantation. April 14, 2014.

Transplant rejection and risk: in search of the genetic dark

Oetting WS, Jacobson PA, Israni AK.
Journal of Gastrointestinal Liver Disease. 2013 Jun;22(2):125-6.

TMaking the genomic leap in HCT: application of second-
generation sequencing to clinical advances in hematopoietic
cell transplantation.

Li YR, Levine JE, Hakonarson H, Keating BJ.
European Journal of Human Genetics. 2014 Jun;22(6):715-23. doi: 10.1038/ejhg.2013.247

Design Papers


International G, Translational Research in Transplantation N. Design and Implementation of the International Genetics and Translational Research in Transplantation Network. Transplantation. 2015;99(11):2401-12. Epub 2015/10/20. doi: 10.1097/TP.0000000000000913. PubMed 26479416

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. Concept and design of a genome-wide association genotyping array tailored for transplantation-specific studies. Genome Med. 2015;7:90. Epub 2015/10/02. doi: 10.1186/s13073-015-0211-x. PubMed 


Fishman CE, Mohebnasab M, van Setten J, Zanoni F, Wang C, Deaglio S, Amoroso A, Callans L, van Gelder T, Lee S, Kiryluk K, Lanktree MB, Keating BJ. Genome-Wide Study Updates in the International Genetics and Translational Research in Transplantation Network (iGeneTRAiN). Front Genet. 2019 Nov 15;10:1084. doi: 10.3389/fgene.2019.01084. eCollection 2019. 


Genetic Association Studies


Robert P O’Brien , Paul J Phelan, Judith Conroy, Patrick O’Kelly, Andrew Green, Mary Keogan, Derek O’Neill, Susan Jennings, Carol Traynor, Jillian Casey, Mark McCormack, Ronan Conroy, Anthony Chubb, Sean Ennis, Denis C Shields, Gianpiero L Cavalleri, Peter J Conlon.  A genome-wide association study of recipient genotype and medium-term kidney allograft function


M Lee Sanders , Jason H Karnes , Josh C Denny , Dan M Roden , T Alp Ikizler , Kelly A Birdwell . Clinical and Genetic Factors Associated with Cutaneous Squamous Cell Carcinoma in Kidney and Heart Transplant Recipients. 


Stapleton CP, Birdwell KA, McKnight AJ, Maxwell AP, Mark PB, Sanders ML, Chapman FA, van Setten J, Phelan PJ, Kennedy C, Jardine A, Traynor JP, Keating B, Conlon PJ, Cavalleri GL. Polygenic risk score as a determinant of risk of non-melanoma skin cancer in a European-descent renal transplant cohort. Am J Transplant. 2019;19(3):801-10. Epub 2018/08/08. doi: 10.1111/ajt.15057. PubMed 


Oetting WS, Schladt DP, Dorr CR, Wu B, Guan W, Remmel RP, Ikle D, Mannon RB, Matas AJ, Israni AK, Jacobson PA, De KAFG, Investigators GEN. Analysis of 75 Candidate SNPs Associated With Acute Rejection in Kidney Transplant Recipients: Validation of rs2910164 in MicroRNA MIR146A. Transplantation. 2019;103(8):1591-602. Epub 2019/02/26. doi: 10.1097/TP.0000000000002659. PubMed 


Stapleton CP, Heinzel A, Guan W, van der Most PJ, van Setten J, Lord GM, Keating BJ, Israni AK, de Borst MH, Bakker SJL, Snieder H, Weale ME, Delaney F, Hernandez-Fuentes MP, Reindl-Schwaighofer R, Oberbauer R, Jacobson PA, Mark PB, Chapman FA, Phelan PJ, Kennedy C, Sexton D, Murray S, Jardine A, Traynor JP, McKnight AJ, Maxwell AP, Smyth LJ, Oetting WS, Matas AJ, Mannon RB, Schladt DP, Ikle DN, Cavalleri GL, Conlon PJ, Consortium UKIRT, De KAFG, Studies GEN, International G, Translational Research in Transplantation N. The impact of donor and recipient common clinical and genetic variation on estimated glomerular filtration rate in a European renal transplant population. Am J Transplant. 2019;19(8):2262-73. Epub 2019/03/29. doi: 10.1111/ajt.15326. PubMed 


Stapleton CP, Chang BL, Keating BJ, Conlon PJ, Cavalleri GL.




Nguyen TT, Pearson RA, Mohamed ME, Schladt DP, Berglund D, Rivers Z, Skaar DJ, Wu B, Guan W, van Setten J, Keating BJ, Dorr C, Remmel RP, Matas AJ, Mannon RB, Israni AK, Oetting WS, Jacobson PA.


Oetting WS, Wu B, Schladt DP, Guan W, Remmel RP, Dorr C, Mannon RB, Matas AJ, Israni AK, Jacobson PA. Attempted validation of 44 reported SNPs associated with tacrolimus troughs in a cohort of kidney allograft recipients. Pharmacogenomics. 2018 Feb;19(3):175-184. doi: 10.2217/pgs-2017-0187. Epub 2018 Jan 10.


Scheibner A, Remmel R, Schladt D, Oetting WS, Guan W, Wu B, Dorr C, Israni A, Jacobson PA. Tacrolimus Elimination in Four Patients With a CYP3A5*3/*3 CYP3A4*22/*22 Genotype Combination. Pharmacotherapy. 2018 May 26:10.1002/phar.2131. doi: 10.1002/phar.2131. 


Seibert SR, Schladt DP, Wu B, Guan W, Dorr C, Remmel RP, Matas AJ, Mannon RB, Israni AK, Oetting WS, Jacobson PA. Tacrolimus trough and dose intra-patient variability and CYP3A5 genotype: Effects on acute rejection and graft failure in European American and African American kidney transplant recipients.


Dorr CR, Wu B, Remmel RP, Muthusamy A, Schladt DP, Abrahante JE, Guan W, Mannon RB, Matas AJ, Oetting WS, Jacobson PA, Israni AK; for DeKAF Genomics. Identification of genetic variants associated with tacrolimus metabolism in kidney transplant recipients by extreme phenotype sampling and next generation sequencing. Pharmacogenomics J. 2019 Aug;19(4):375-389. doi: 10.1038/s41397-018-0063-z. Epub 2018 Nov 16.


Oetting WS, Wu B, Schladt DP, Guan W, van Setten J, Keating BJ, Ikle D, Remmel RP, Dorr CR, Mannon RB, Matas AJ, Israni AK, Jacobson PA, De KAFG, Investigators GEN. Genetic Variants Associated With Immunosuppressant Pharmacokinetics and Adverse Effects in the DeKAF Genomics Genome-wide Association Studies. Transplantation. 2019;103(6):1131-9. Epub 2019/02/26. doi: 10.1097/TP.0000000000002625.


Mohamed ME, Schladt DP, Guan W, Wu B, van Setten J, Keating BJ, Ikle D, Remmel RP, Dorr CR, Mannon RB, Matas AJ, Israni AK, Oetting WS, Jacobson PA, De KAFG, Investigators GEN. Tacrolimus troughs and genetic determinants of metabolism in kidney transplant recipients: A comparison of four ancestry groups. Am J Transplant. 2019. Epub 2019/04/07. doi: 10.1111/ajt.15385




Shaked A, Chang BL, Barnes MR, Sayre P, Li YR, Asare S, DesMarais M, Holmes MV, Guettouche T, Keating BJ. An ectopically expressed serum miRNA signature is prognostic, diagnostic, and biologically related to liver allograft rejection. Hepatology. 2017 Jan;65(1):269-280. doi: 10.1002/hep.28786. Epub 2016 Oct 5.


Romero E, Chang E, Tabak E, Pinheiro D, Tallaj J, Litovsky S, Keating B, Deng M, Cadeiras M.


Wu JF, Muthusamy A, Al-Ghalith GA, Knights D, Guo B, Wu B, Remmel RP, Schladt DP, Alegre ML, Oetting WS, Jacobson PA, Israni AK. Urinary microbiome associated with chronic allograft dysfunction in kidney transplant recipients. Clin Transplant. 2018 Dec;32(12):e13436. doi: 10.1111/ctr.13436. Epub 2018 Nov 18.


Primary Disease


Snoek R, van Setten J, Keating BJ, Israni AK, Jacobson PA, Oetting WS, Matas AJ, Mannon RB, Zhang Z, Zhang W, Hao K, Murphy B, Reindl-Schwaighofer R, Heinzl A, Oberbauer R, Viklicky O, Conlon PJ, Stapleton CP, Bakker SJL, Snieder H, Peters EDJ, van der Zwaag B, Knoers N, de Borst MH, van Eerde AM. NPHP1 (Nephrocystin-1) Gene Deletions Cause Adult-Onset ESRD. J Am Soc Nephrol. 2018;29(6):1772-9. Epub 2018/04/15. doi: 10.1681/ASN.2017111200. PubMed 


Cyrus C, Al-Mueilo S, Vatte C, Chathoth S, Li YR, Qutub H, Al Ali R, Al-Muhanna F, Lanktree MB, Alkharsah KR, Al-Rubaish A, Kim-Mozeleski B, Keating B, Al Ali A. Assessing known chronic kidney disease associated genetic variants in Saudi Arabian populations.




Dorr CR, Oetting WS, Jacobson PA, Israni AK. Genetics of acute rejection after kidney transplantation. Transpl Int. 2018 Mar;31(3):263-277. doi: 10.1111/tri.13084. Epub 2017 Nov 8.


Oetting WS, Dorr C, Remmel RP, Matas AJ, Israni AK, Jacobson PA. Concepts of Genomics in Kidney Transplantation. Curr Transplant Rep. 2017 Jun;4(2):116-123. doi: 10.1007/s40472-017-0153-x. Epub 2017 May 24.


Keating BJ, Pereira AC, Snyder M, Piening BD. Applying genomics in heart transplantation. Transpl Int. 2018;31(3):278-90. Epub 2018/01/25. doi: 10.1111/tri.13119.


Zhu A, Leto A, Shaked A, Keating B. Immunologic Monitoring to Personalize Immunosuppression After Liver Transplant. Gastroenterol Clin North Am. 2018;47(2):281-96. Epub 2018/05/08. doi: 10.1016/j.gtc.2018.01.003. PubMed 


Mohebnasab M, Eriksson O, Persson B, Sandholm K, Mohlin C, Huber-Lang M, Keating BJ, Ekdahl KN, Nilsson B.


Kohut TJ, Barandiaran JF, Keating BJ. Genomics and Liver Transplantation: Genomic Biomarkers for the Diagnosis of Acute Cellular Rejection


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