GEnetics of Nephropathy - an International Effort (GENIE) GWAS of Diabetic Nephropathy in the UK GoKinD and All-Ireland Cohorts

Diabetic kidney disease, or diabetic nephropathy (DN), is one of the leading causes of end-stage renal disease in the United States and worldwide. DN is a common complication of long-standing type 1 and type 2 diabetes. The clinical course is characterized by development of proteinuria and gradual loss of kidney function. Although existing treatments that decrease proteinuria have been shown to moderately abate progression of diabetic kidney disease, many affected patients, who do not die from cardiovascular disease, go on to develop terminal renal failure, necessitating costly renal replacement therapies, such as dialysis and renal transplantation. Type 1 diabetes (T1D) can have its onset in childhood and affected individuals often develop end-stage renal disease in early adulthood, leading to further loss of quality of life. The genetic basis of the disease is not well understood.

The GENIE (GEnetics of Nephropathy an International Effort) consortium was initiated to perform the most comprehensive and well powered DN susceptibility genome wide association study (GWAS) analysis to date, using the largest collection of type 1 diabetics with and without kidney disease across four study cohorts. The UK-ROI samples were genotyped as part of this project.

UK-ROI Sample Description
The UK-ROI collection consists of samples derived from the Republic of Ireland (Dr. Catherine Godson, PI, at University College, Dublin, Ireland) and the United Kingdom (Warren 3 and Genetics of Kidneys in Diabetes UK, UK GoKinD, Dr. Alexander P. Maxwell, PI, at Queen's University of Belfast, UK). All study subjects met the inclusion criteria: white individuals with T1D, diagnosed before 31 years of age, whose parents and grandparents were born in the British Isles.

• Study Design:
  • Case-Control
• Study Type:
  • Case-Control
• dbGaP estimated ancestry using GRAF-pop
• Total number of consented subjects: 1801
• Subject Sample Telemetry Report (SSTR)

• BioProject
• PubMed
• BioSample
• MeSH
• PMC

Case Definition: individuals with end stage renal disease (ESRD; defined as those requiring renal replacement therapy or having received a kidney transplant) or persistent proteinuria (>0.5 g/24 hr) developing more than 10 years after the diagnosis of type 1 diabetes. 903 individuals formed the case group.

Controls Definition: individuals with absence of DN, defined as persistent normoalbuminuria (2 out of 3 albumin creatinine ratio (ACR) measurements <20 µg of albumin/mg of creatinine) despite duration of T1D for at least 15 years, not taking an antihypertensive medication, and having no history of treatment with ACE inhibitors; 1,001 individuals formed the control group.

Additionally, the following variables and covariates were utilized in the analyses in the study and are provided to ensure consistency of findings for dbGaP users with original analyses:

2001: An All Ireland DNA resource (267 cases and 442 controls) was created to investigate genetic predisposition to diabetic nephropathy in carefully phenotyped individuals. A complementary UK resource also received ethical approval to recruit individuals using similar phenotypic criteria to the All Ireland collection; this was jointly funded by Diabetes UK and the Juvenile Diabetes Foundation.

2008: The Warren 3 - GoKinD UK (597 cases, 502 controls) and All Ireland combined collection of DNA was available for inclusion in genetic studies investigating diabetic nephropathy.

Following the completion of focused loci and low-resolution genome-wide association studies in these collections, the GENIE consortium was established to evaluate genetic susceptibility for diabetic nephropathy in worldwide collections.

2011: Completion of genotyping in 1,830 individuals on the Omni1-quad from the All Ireland-Warren3-GoKinD UK resource [data released here].

• Primary Phenotype: Diabetes Mellitus, Type 1
• Diabetic Nephropathy
• Kidney Failure, Chronic
• Albuminuria
• Diabetes Complications

• Principal Investigators
  • Joel Hirschhorn. Broad Institute and Children's Hospital Boston, Boston, MA, USA.
  • Alexander P. Maxwell. Queen's University, Belfast, UK.
  • Catherine Godson. University College, Dublin, Ireland.
  • Jose Florez. Massachusetts General Hospital, Boston, MA, USA.
• Lead Analysts
  • Amy Jayne McKnight. Queen's University, Belfast, UK.
  • Rany Salem. Broad Institute and Children's Hospital Boston, Boston, MA, USA.
• Co-Investigators
  • Denise Sadlier. University College, Dublin, Ireland.
  • Eoin Brennan. University College, Dublin, Ireland.
• Institutions
  • Mater Misericordiae Hospital, Dublin, Ireland.
  • University College Dublin, Dublin, Ireland.
  • Queen's University, Belfast, UK.
• Project Managers
  • Candace Guiducci. Broad Institute and Children's Hospital Boston, Boston, MA, USA.
  • Daniel Mirel. Broad Institute and Children's Hospital Boston, Boston, MA, USA.
• Analyst
  • Tamara Isacova. Massachusetts General Hospital, Boston, MA, USA.
• Funding Source
  • Northern Ireland Research and Development office; US-Ireland R and D partnership.
  • Diabetes UK.
  • Science Foundation Ireland; US-Ireland R and D partnership.
  • Juvenile Diabetes Research Foundation International.
  • 5R01DK081923. National Institutes of Health, Bethesda, MD, USA.