Novel genetic susceptibility loci for diabetic end-stage renal disease identified through robust naive Bayes classification

The GENIE Consortium, The FinnDiane Study Group

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Aims/hypothesis: 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. Methods: 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). Results: 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. Conclusions/interpretation: 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.
Original languageEnglish
Pages (from-to)1611-1622
JournalDiabetologia
Volume57
Issue number8
Early online date29 May 2014
DOIs
Publication statusPublished - Aug 2014

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Genetic Loci
Genetic Predisposition to Disease
Diabetic Nephropathies
Chronic Kidney Failure
Type 1 Diabetes Mellitus
Ireland
Kidney
Genome-Wide Association Study
Diabetes Complications
Genes
Genome

Cite this

The GENIE Consortium ; The FinnDiane Study Group. / Novel genetic susceptibility loci for diabetic end-stage renal disease identified through robust naive Bayes classification. In: Diabetologia. 2014 ; Vol. 57, No. 8. pp. 1611-1622.
@article{6d09b37f353a4601bdbfa8cddfd8fd82,
title = "Novel genetic susceptibility loci for diabetic end-stage renal disease identified through robust naive Bayes classification",
abstract = "Aims/hypothesis: 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. Methods: 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). Results: 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. Conclusions/interpretation: 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.",
author = "Francesco Sambo and Alberto Malovini and Niina Sandholm and Monica Stavarachi and Carol Forsblom and Ville-Petteri M{\"a}kinen and Valma Harjutsalo and Raija Lithovius and Daniel Gordin and Maija Parkkonen and Markku Saraheimo and Thorn, {Lena M} and Nina Tolonen and Johan Wad{\'e}n and Bing He and Anne-May Osterholm and Jaako Tuomilehto and Maria Lajer and Salem, {Rany M} and McKnight, {Amy Jayne} and Lise Tarnow and Panduru, {Nicolae M} and Nicola Barbarini and {Di Camillo}, Barbara and Toffolo, {Gianna M} and Karl Tryggvason and Riccardo Bellazzi and Claudio Cobelli and Per-Henrik Groop and {The GENIE Consortium} and {The FinnDiane Study Group}",
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Novel genetic susceptibility loci for diabetic end-stage renal disease identified through robust naive Bayes classification. / The GENIE Consortium; The FinnDiane Study Group.

In: Diabetologia, Vol. 57, No. 8, 08.2014, p. 1611-1622.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Novel genetic susceptibility loci for diabetic end-stage renal disease identified through robust naive Bayes classification

AU - Sambo, Francesco

AU - Malovini, Alberto

AU - Sandholm, Niina

AU - Stavarachi, Monica

AU - Forsblom, Carol

AU - Mäkinen, Ville-Petteri

AU - Harjutsalo, Valma

AU - Lithovius, Raija

AU - Gordin, Daniel

AU - Parkkonen, Maija

AU - Saraheimo, Markku

AU - Thorn, Lena M

AU - Tolonen, Nina

AU - Wadén, Johan

AU - He, Bing

AU - Osterholm, Anne-May

AU - Tuomilehto, Jaako

AU - Lajer, Maria

AU - Salem, Rany M

AU - McKnight, Amy Jayne

AU - Tarnow, Lise

AU - Panduru, Nicolae M

AU - Barbarini, Nicola

AU - Di Camillo, Barbara

AU - Toffolo, Gianna M

AU - Tryggvason, Karl

AU - Bellazzi, Riccardo

AU - Cobelli, Claudio

AU - Groop, Per-Henrik

AU - The GENIE Consortium

AU - The FinnDiane Study Group

PY - 2014/8

Y1 - 2014/8

N2 - Aims/hypothesis: 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. Methods: 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). Results: 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. Conclusions/interpretation: 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.

AB - Aims/hypothesis: 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. Methods: 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). Results: 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. Conclusions/interpretation: 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.

U2 - 10.1007/s00125-014-3256-2

DO - 10.1007/s00125-014-3256-2

M3 - Article

C2 - 24871321

VL - 57

SP - 1611

EP - 1622

JO - Diabetologia

JF - Diabetologia

SN - 0012-186X

IS - 8

ER -