Novel genetic susceptibility loci for diabetic end-stage renal disease identified through robust naive Bayes classification
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Diabetic nephropathy is a major diabetic complication, and diabetes is the leading cause of end-stage renal disease (ESRD). Family studies suggest a hereditary component for diabetic nephropathy. However, only a few genes have been associated with diabetic nephropathy or ESRD in diabetic patients. Our aim was to detect novel genetic variants associated with diabetic nephropathy and ESRD.
We exploited a novel algorithm, ‘Bag of Naive Bayes’, whose marker selection strategy is complementary to that of conventional genome-wide association models based on univariate association tests. The analysis was performed on a genome-wide association study of 3,464 patients with type 1 diabetes from the Finnish Diabetic Nephropathy (FinnDiane) Study and subsequently replicated with 4,263 type 1 diabetes patients from the Steno Diabetes Centre, the All Ireland-Warren 3-Genetics of Kidneys in Diabetes UK collection (UK–Republic of Ireland) and the Genetics of Kidneys in Diabetes US Study (GoKinD US).
Five genetic loci (WNT4/ZBTB40-rs12137135, RGMA/MCTP2-rs17709344, MAPRE1P2-rs1670754, SEMA6D/SLC24A5-rs12917114 and SIK1-rs2838302) were associated with ESRD in the FinnDiane study. An association between ESRD and rs17709344, tagging the previously identified rs12437854 and located between the RGMA and MCTP2 genes, was replicated in independent case–control cohorts. rs12917114 near SEMA6D was associated with ESRD in the replication cohorts under the genotypic model (p < 0.05), and rs12137135 upstream of WNT4 was associated with ESRD in Steno.
This study supports the previously identified findings on the RGMA/MCTP2 region and suggests novel susceptibility loci for ESRD. This highlights the importance of applying complementary statistical methods to detect novel genetic variants in diabetic nephropathy and, in general, in complex diseases.
KeywordsBag of Naive Bayes Diabetic nephropathy End-stage renal disease Susceptibility loci
Body adiposity index
Bag of Naive Bayes
Diastolic blood pressure
End-stage renal disease
False discovery rate
Finnish Diabetic Nephropathy Study
Genetics of Nephropathy–an International Effort
- GoKinD US
Genetics of Kidneys in Diabetes US Study
Genome-wide association study
Matthews correlation coefficient
Naive Bayes classifier
Systolic blood pressure
Single nucleotide polymorphism
All Ireland-Warren 3-Genetics of Kidneys in Diabetes UK collection (UK and Republic of Ireland)
We thank M. Parkkonen, A. Sandelin, A.-Reetta Salonen, T. Soppela and J. Tuomikangas for skilful laboratory assistance. We also thank all the patients who participated in the study and gratefully acknowledge all the physicians and nurses at each centre involved in the recruitment of participants (ESM Table 5). The members of the GENIE Consortium are listed in ESM Table 6.
The FinnDiane Study was supported by grants from the Folkhälsan Research Foundation, the Wilhelm and Else Stockmann Foundation, the Liv och Hälsa Foundation, Helsinki University Central Hospital Research Funds (EVO), the Sigrid Juselius Foundation, the Signe and Arne Gyllenberg Foundation, Finska Läkaresällskapet, the Novo Nordisk Foundation, the Academy of Finland (134379) and Tekes. The research was supported by the European Union's Seventh Framework Program (FP7/2007-2013) for the Innovative Medicine Initiative under grant agreement IMI/115006 (the SUMMIT consortium). The GENIE consortium was funded by National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (NIH NIDDK) R01DK081923 and the Northern Ireland Research and Development Office. M. Stavarachi was supported by the Sectoral Operational Programme Human Resources Development (SOP HRD), financed from the European Social Fund and by the Romanian Government under contract number POSDRU/89/1.5/S/64109. V.-P. Mäkinen was supported by American Heart Association (13POST17240095).
Duality of interest
P-HG has received lecture honoraria from Abbot, Boehringer Ingelheim, Cebix, Eli Lilly, Genzyme, Novartis, Novo Nordisk and MSD, and research grants from Eli Lilly, Roche. P-HG is also an advisory board member for Boehringer Ingelheim, Novartis and Medscape.
FS, AM, NS and M. Stavarachi analysed data and wrote the manuscript. CF contributed to the conception and design and acquisition of data, and revised the manuscript critically. V-PM contributed to the conception and design and revised the manuscript critically. VH, RL, DG, MP, M. Saraheimo, LMT, NT, JW, BH, A-MÖ, JT, ML, AJM, LT, KT, NMP and P-HG contributed to the acquisition of the genotypic and/or phenotypic data and revised the manuscript critically. RMS and AJM analysed data and revised the manuscript. NB, BD and GMT contributed to the interpretation of the results, revised and edited the manuscript. RB, CC and P-HG designed and supervised the study and revised the manuscript. All the authors approved the final version of the manuscript. P-HG is the guarantor of this work.
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