Genome-wide association study of diabetic kidney disease highlights biology involved in renal basement membrane collagen Article Swipe

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Rany M. Salem , Jennifer N. Todd , Niina Sandholm , Joanne B. Cole , Wei‐Min Chen , Darrel Andrews , Marcus G. Pezzolesi , Paul McKeigue , Linda T. Hiraki , Chengxiang Qiu , Viji Nair , Chen Di Liao , Jing Cao , Erkka Valo , Suna Önengüt-Gümüşcü , Adam M. Smiles , Stuart J. McGurnaghan , Jani K. Haukka , Valma Harjutsalo , Eoin Brennan , Natalie Van Zuydam , Emma Ahlqvist , Ross Doyle , Tarunveer S. Ahluwalia , Maria Lajer , Maria Hughes , Jihwan Park , Jan Skupień , Athina Spiliopoulou , Andy Liu , Rajasree Menon , Carine M. Boustany‐Kari , Hyun Min Kang , Robert G. Nelson , Ronald Klein , Barbara E.K. Klein , Kristine E. Lee , Xiaoyu Gao , Michael Mauer , Silvia Maeastroni , Maria Luiza Caramori , Ian H. de Boer , Rachel G. Miller , Jingchuan Guo , Andrew P. Boright , David‐Alexandre Trégouët , Beata Gyorgy , Janet K. Snell‐Bergeon , David M. Maahs , Shelley B. Bull , Angelo J. Canty , Colin N.A. Palmer , Lars Stechemesser , Bernhard Paulweber , Raimund Weitgasser , Jeļizaveta Sokolovska , Vita Rovīte , Valdis Pīrāgs , Edita Prakapienė , Lina Radzevičienė , Rasa Verkauskienė , Nicolae Mircea Panduru , Leif Groop , Mark I. McCarthy , Harvest F. Gu , Anna Möllsten , Henrik Falhammar , Kerstin Brismar , Finian Martin , Peter Rossing , Tina Costacou , Gianpaolo Zerbini , Michel Marre , Samy Hadjadj , Amy Jayne McKnight , Carol Forsblom , Gareth J. McKay , Catherine Godson , Alexander P. Maxwell , Matthias Kretzler , Katalin Suszták , Helen M. Colhoun , Andrzej S. Królewski , Andrew D. Paterson , Per‐Henrik Groop , Stephen S. Rich , Joel N. Hirschhorn , José C. Florez ·

YOU? · · 2018 · Open Access · · DOI: https://doi.org/10.1101/499616

Diabetic kidney disease (DKD) is a heritable but poorly understood complication of diabetes. To identify genetic variants predisposing to DKD, we performed genome-wide association analyses in 19,406 individuals with type 1 diabetes (T1D) using a spectrum of DKD definitions basedon albuminuria and renal function. We identified 16 genome-wide significant loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain (COL4A3) gene, which encodes a major structural component of the glomerular basement membrane (GBM) implicated in heritable nephropathies. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of DKD, including albuminuria and end-stage renal disease. Three other loci are in or near genes with known or suggestive involvement in DKD (BMP7) or renal biology ( COLEC11 and DDR1 ). The 16 DKD-associated loci provide novel insights into the pathogenesis of DKD, identifying potential biological targets for prevention and treatment.

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Genome-Wide Association Study

Concepts

Albuminuria Glomerular basement membrane Missense mutation Genome-wide association study Disease Alport syndrome Diabetic nephropathy Genetic association Pathogenesis Genetics Biology Kidney disease Medicine Bioinformatics Mutation Gene Kidney Single-nucleotide polymorphism Pathology Internal medicine Genotype Glomerulonephritis

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Type: preprint
Language: en
Landing Page: https://doi.org/10.1101/499616
PDF: https://www.biorxiv.org/content/biorxiv/early/2018/12/19/499616.full.pdf
OA Status: green
Cited By: 12
References: 91
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DOI: https://doi.org/10.1101/499616

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Title: Genome-wide association study of diabetic kidney disease highlights biology involved in renal basement membrane collagen

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Type: preprint

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Language: en

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Publication year: 2018

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Publication date: 2018-12-19

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Authors: Rany M. Salem, Jennifer N. Todd, Niina Sandholm, Joanne B. Cole, Wei‐Min Chen, Darrel Andrews, Marcus G. Pezzolesi, Paul McKeigue, Linda T. Hiraki, Chengxiang Qiu, Viji Nair, Chen Di Liao, Jing Cao, Erkka Valo, Suna Önengüt-Gümüşcü, Adam M. Smiles, Stuart J. McGurnaghan, Jani K. Haukka, Valma Harjutsalo, Eoin Brennan, Natalie Van Zuydam, Emma Ahlqvist, Ross Doyle, Tarunveer S. Ahluwalia, Maria Lajer, Maria Hughes, Jihwan Park, Jan Skupień, Athina Spiliopoulou, Andy Liu, Rajasree Menon, Carine M. Boustany‐Kari, Hyun Min Kang, Robert G. Nelson, Ronald Klein, Barbara E.K. Klein, Kristine E. Lee, Xiaoyu Gao, Michael Mauer, Silvia Maeastroni, Maria Luiza Caramori, Ian H. de Boer, Rachel G. Miller, Jingchuan Guo, Andrew P. Boright, David‐Alexandre Trégouët, Beata Gyorgy, Janet K. Snell‐Bergeon, David M. Maahs, Shelley B. Bull, Angelo J. Canty, Colin N.A. Palmer, Lars Stechemesser, Bernhard Paulweber, Raimund Weitgasser, Jeļizaveta Sokolovska, Vita Rovīte, Valdis Pīrāgs, Edita Prakapienė, Lina Radzevičienė, Rasa Verkauskienė, Nicolae Mircea Panduru, Leif Groop, Mark I. McCarthy, Harvest F. Gu, Anna Möllsten, Henrik Falhammar, Kerstin Brismar, Finian Martin, Peter Rossing, Tina Costacou, Gianpaolo Zerbini, Michel Marre, Samy Hadjadj, Amy Jayne McKnight, Carol Forsblom, Gareth J. McKay, Catherine Godson, Alexander P. Maxwell, Matthias Kretzler, Katalin Suszták, Helen M. Colhoun, Andrzej S. Królewski, Andrew D. Paterson, Per‐Henrik Groop, Stephen S. Rich, Joel N. Hirschhorn, José C. Florez

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Concepts: Albuminuria, Glomerular basement membrane, Missense mutation, Genome-wide association study, Disease, Alport syndrome, Diabetic nephropathy, Genetic association, Pathogenesis, Genetics, Biology, Kidney disease, Medicine, Bioinformatics, Mutation, Gene, Kidney, Single-nucleotide polymorphism, Pathology, Internal medicine, Genotype, Glomerulonephritis

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Cited by: 12

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abstract_inverted_index.Diabetic	0
abstract_inverted_index.analyses	24
abstract_inverted_index.basement	81
abstract_inverted_index.collagen	64
abstract_inverted_index.diabetes	31
abstract_inverted_index.disease.	105
abstract_inverted_index.identify	14
abstract_inverted_index.insights	136
abstract_inverted_index.membrane	82
abstract_inverted_index.missense	60
abstract_inverted_index.mutation	61
abstract_inverted_index.spectrum	35
abstract_inverted_index.variants	16
abstract_inverted_index.component	77
abstract_inverted_index.diabetes.	12
abstract_inverted_index.end-stage	103
abstract_inverted_index.function.	43
abstract_inverted_index.heritable	6, 86
abstract_inverted_index.including	100
abstract_inverted_index.performed	21
abstract_inverted_index.potential	143
abstract_inverted_index.strongest	54
abstract_inverted_index.biological	144
abstract_inverted_index.glomerular	80
abstract_inverted_index.identified	45
abstract_inverted_index.implicated	84
abstract_inverted_index.prevention	147
abstract_inverted_index.protective	94
abstract_inverted_index.rs55703767	89
abstract_inverted_index.structural	76
abstract_inverted_index.suggestive	117
abstract_inverted_index.treatment.	149
abstract_inverted_index.understood	9
abstract_inverted_index.(Asp326Tyr)	92
abstract_inverted_index.albuminuria	40, 101
abstract_inverted_index.association	23, 55
abstract_inverted_index.definitions	38, 97
abstract_inverted_index.genome-wide	22, 47
abstract_inverted_index.identifying	142
abstract_inverted_index.individuals	27
abstract_inverted_index.involvement	118
abstract_inverted_index.significant	48
abstract_inverted_index.(rs55703767)	56
abstract_inverted_index.complication	10
abstract_inverted_index.pathogenesis	139
abstract_inverted_index.predisposing	17
abstract_inverted_index.DKD-associated	132
abstract_inverted_index.nephropathies.	87
cited_by_percentile_year.max	97
cited_by_percentile_year.min	89
countries_distinct_count	15
institutions_distinct_count	88
sustainable_development_goals[0].id	https://metadata.un.org/sdg/3
sustainable_development_goals[0].score	0.8399999737739563
sustainable_development_goals[0].display_name	Good health and well-being
citation_normalized_percentile.value	0.79646412
citation_normalized_percentile.is_in_top_1_percent	False
citation_normalized_percentile.is_in_top_10_percent	False