Design and Implementation of the International Genetics and Translational Research in Transplantation Network

Abstract

Background: Genetic association studies of transplantation outcomes have been hampered by small samples and highly complex multifactorial phenotypes, hindering investigations of the genetic architecture of a range of comorbidities which significantly impact graft and recipient life expectancy. We describe here the rationale and design of the International Genetics & Translational Research in Transplantation Network. The network comprises 22 studies to date, including 16494 transplant recipients and 11669 donors, of whom more than 5000 are of non-European ancestry, all of whom have existing genomewide genotype data sets.

Methods: We describe the rich genetic and phenotypic information available in this consortium comprising heart, kidney, liver, and lung transplant cohorts.

Results: We demonstrate significant power in International Genetics & Translational Research in Transplantation Network to detect main effect association signals across regions such as the MHC region as well as genomewide for transplant outcomes that span all solid organs, such as graft survival, acute rejection, new onset of diabetes after transplantation, and for delayed graft function in kidney only.

Conclusions: This consortium is designed and statistically powered to deliver pioneering insights into the genetic architecture of transplant-related outcomes across a range of different solid-organ transplant studies. The study design allows a spectrum of analyses to be performed including recipient-only analyses, donor-recipient HLA mismatches with focus on loss-of-function variants and nonsynonymous single nucleotide polymorphisms.

FIGURE 1

Statistical power calculations to detect main effects for the four main iGeneTRAiN phenotypes across the Major Histocompatibility Complex. Graft Survival in 4800 cases and 11,250 controls (top-left); AR in 3250 cases and 12,400 controls (bottom-left); NODAT in 1400 cases and 14,500 controls (top-right); DGF in 1,020 cases and 8,900 controls (kidney only) (bottom-right). The X-axes shows the OR effect size, and the Y-axes illustrate the statistical power to detect the main effects under different MAFs: 5%, 10%, 20%, and 30% shown in blue, red, green, and purple, respectively. The models are additive model in recipients and assume approximately 20,000 tests (Bonferroni correction 0.05). OR indicates odds ratio; MAFs, minor allele frequencies.

FIGURE 2

Genome-wide statistical power calculations to detect main effects for the four main iGeneTRAiN phenotypes. Graft Survival in 4800 cases and 11,250 controls (top-left); AR in 3250 cases and 12,400 controls (bottom-left); NODAT in 1400 cases and 14,500 controls (top-right); DGF in 1020 cases and 8900 controls (kidney only) (bottom-right). The X-axes shows the OR effect size, and the Y-axes illustrate the statistical power to detect the main effects under different MAFs: 5%, 10%, 20%, and 30% shown in blue, red, green, and purple, respectively. Significance is assessed at 5% level using Bonferroni correction, assuming 500,000 SNP tests