title: The Genetic Landscape of Renal Complications in Type 1 Diabetes.
abstract: Diabetes is the leading cause of ESRD. Despite evidence for a substantial heritability of diabetic kidney disease, efforts to identify genetic susceptibility variants have had limited success. We extended previous efforts in three dimensions, examining a more comprehensive set of genetic variants in larger numbers of subjects with type 1 diabetes characterized for a wider range of cross-sectional diabetic kidney disease phenotypes. In 2843 subjects, we estimated that the heritability of diabetic kidney disease was 35% (P=6.4×10-3). Genome-wide association analysis and replication in 12,540 individuals identified no single variants reaching stringent levels of significance and, despite excellent power, provided little independent confirmation of previously published associated variants. Whole-exome sequencing in 997 subjects failed to identify any large-effect coding alleles of lower frequency influencing the risk of diabetic kidney disease. However, sets of alleles increasing body mass index (P=2.2×10-5) and the risk of type 2 diabetes (P=6.1×10-4) associated with the risk of diabetic kidney disease. We also found genome-wide genetic correlation between diabetic kidney disease and failure at smoking cessation (P=1.1×10-4). Pathway analysis implicated ascorbate and aldarate metabolism (P=9.0×10-6), and pentose and glucuronate interconversions (P=3.0×10-6) in pathogenesis of diabetic kidney disease. These data provide further evidence for the role of genetic factors influencing diabetic kidney disease in those with type 1 diabetes and highlight some key pathways that may be responsible. Altogether these results reveal important biology behind the major cause of kidney disease.
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.|Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.|Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
authors.forename: Niina
authors.initials: N
authors.lastname: Sandholm
authors.affiliation: Wellcome Trust Centre for Human Genetics|Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom.|Medical Research Institute
authors.forename: Natalie
authors.initials: N
authors.lastname: Van Zuydam
authors.affiliation: Department of Clinical Sciences, Diabetes and Endocrinology, Skåne University Hospital, Lund University, Malmö, Sweden.
authors.forename: Emma
authors.initials: E
authors.lastname: Ahlqvist
authors.affiliation: Wellcome Trust Centre for Human Genetics
authors.forename: Thorhildur
authors.initials: T
authors.lastname: Juliusdottir
authors.affiliation: Division of Population Health Sciences, University of Dundee, Dundee, United Kingdom.
authors.forename: Harshal A
authors.initials: HA
authors.lastname: Deshmukh
authors.affiliation: Wellcome Trust Centre for Human Genetics|Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom.|Human Genetics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: N William
authors.initials: NW
authors.lastname: Rayner
authors.affiliation: Department of Information Engineering, University of Padova, Padova, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Di Camillo
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.|Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.|Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
authors.forename: Carol
authors.initials: C
authors.lastname: Forsblom
authors.affiliation: Department of Clinical Sciences, Diabetes and Endocrinology, Skåne University Hospital, Lund University, Malmö, Sweden.
authors.forename: Joao
authors.initials: J
authors.lastname: Fadista
authors.affiliation: Computational Sciences, Pfizer Worldwide Research and Development, Berlin, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ziemek
authors.affiliation: Departments of Genetics|Programs in Metabolism and Medical and Population Genetics, Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts.|Divisions of Endocrinology and Genetics, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Rany M
authors.initials: RM
authors.lastname: Salem
authors.affiliation: Genetics and Genome Biology Program, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Linda T
authors.initials: LT
authors.lastname: Hiraki
authors.affiliation: Section on Genetics and Epidemiology, Joslin Diabetes Center, Boston, Massachusetts.
authors.forename: Marcus
authors.initials: M
authors.lastname: Pezzolesi
authors.affiliation: Sorbonne Universities, Pierre et Marie Curie University (UPMC) and National Institute for Health and Medical Research, Mixed Research Unit in Health (UMR_S) 1166, Paris, France.|Institute for Cardiometabolism and Nutrition, Genomics and pathophysiology of Cardiovascular diseases, Paris, France.
authors.forename: David
authors.initials: D
authors.lastname: Trégouët
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.|Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.|Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
authors.forename: Emma
authors.initials: E
authors.lastname: Dahlström
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.|Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.|Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
authors.forename: Erkka
authors.initials: E
authors.lastname: Valo
authors.affiliation: Department of Clinical Sciences, Diabetes and Endocrinology, Skåne University Hospital, Lund University, Malmö, Sweden.
authors.forename: Nikolay
authors.initials: N
authors.lastname: Oskolkov
authors.affiliation: Department of Clinical Sciences, Diabetes and Endocrinology, Skåne University Hospital, Lund University, Malmö, Sweden.
authors.forename: Claes
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authors.affiliation: Department of Paediatrics, Institute of Metabolic Science, and.
authors.forename: M Loredana
authors.initials: ML
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authors.affiliation: Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Jason
authors.initials: J
authors.lastname: Cooper
authors.affiliation: Department of Information Engineering, University of Padova, Padova, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Sambo
authors.affiliation: Department of Electrical, Computer and Biomedical Engineering, University of Pavia, Pavia, Italy.|Laboratory of Informatics and Systems Engineering for Clinical Research, Scientific Institute for Research, Hospitalization and Health Care, IRCCS (Instituto di Ricovero e Cura a Carattere Scientifico); Salvatore Maugeri Foundation, Pavia, Italy.
authors.forename: Alberto
authors.initials: A
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authors.affiliation: Department of Information Engineering, University of Padova, Padova, Italy.
authors.forename: Marco
authors.initials: M
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authors.affiliation: Nephrology Research, Centre for Public Health, Queen's University of Belfast, Belfast, United Kingdom.
authors.forename: Amy Jayne
authors.initials: AJ
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authors.affiliation: Diabetic Complications, Steno Diabetes Center, Gentofte, Denmark.
authors.forename: Maria
authors.initials: M
authors.lastname: Lajer
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.|Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.|Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.|The Chronic Disease Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Valma
authors.initials: V
authors.lastname: Harjutsalo
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.|Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.|Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gordin
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.|Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.|Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
authors.forename: Maija
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authors.affiliation: The Chronic Disease Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland.|Centre for Vascular Prevention, Danube University Krems, Krems, Austria
authors.forename: Jaakko
authors.initials: J
authors.lastname: Tuomilehto
authors.affiliation: Department of Clinical Sciences, Diabetes and Endocrinology, Skåne University Hospital, Lund University, Malmö, Sweden.|Diabetic Complications, Steno Diabetes Center, Gentofte, Denmark.
authors.forename: Valeriya
authors.initials: V
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authors.affiliation: Centre for Population Health Sciences, University of Edinburgh, Edinburgh, United Kingdom.
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authors.initials: PM
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authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia.
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authors.initials: SS
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authors.affiliation: Cardiovascular and Metabolic Diseases Research Unit, and.
authors.forename: Mary Julia
authors.initials: MJ
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authors.affiliation: Computational Sciences, Pfizer Worldwide Research and Development, Cambridge, Massachusetts.
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authors.initials: E
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authors.affiliation: Department of Electrical, Computer and Biomedical Engineering, University of Pavia, Pavia, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Bellazzi
authors.affiliation: Diabetic Complications, Steno Diabetes Center, Gentofte, Denmark.|Department of Health, Aarhus University, Aarhus, Denmark.|Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Rossing
authors.affiliation: Functional Research Unit of Medicine and Pharmacy, University of Poitiers, Poitiers, France.|Department of Endocrinology-Diabetology and Center of Clinical Investigation, Poitiers University Hospital, Poitiers, France.|Institute National pour la Santé et la Recherche Médicale, National Institute for Health and Medical Research, Center of Clinical Investigation 1402 and Unit 1082, Poitiers, France.
authors.forename: Samy
authors.initials: S
authors.lastname: Hadjadj
authors.affiliation: Section on Genetics and Epidemiology, Joslin Diabetes Center, Boston, Massachusetts.
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authors.initials: A
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authors.affiliation: Genetics and Genome Biology Program, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Andrew D
authors.initials: AD
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authors.affiliation: Programs in Metabolism and Medical and Population Genetics, Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts.|Diabetes Unit and Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts
authors.forename: Jose C
authors.initials: JC
authors.lastname: Florez
authors.affiliation: Departments of Genetics|Programs in Metabolism and Medical and Population Genetics, Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts.|Divisions of Endocrinology and Genetics, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Joel N
authors.initials: JN
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authors.affiliation: Nephrology Research, Centre for Public Health, Queen's University of Belfast, Belfast, United Kingdom.|Regional Nephrology Unit, Belfast City Hospital, Belfast, United Kingdom; and.
authors.forename: Alexander P
authors.initials: AP
authors.lastname: Maxwell
authors.affiliation: Department of Paediatrics, Institute of Metabolic Science, and.
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authors.initials: D
authors.lastname: Dunger
authors.affiliation: Department of Information Engineering, University of Padova, Padova, Italy.
authors.forename: Claudio
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authors.affiliation: Division of Population Health Sciences, University of Dundee, Dundee, United Kingdom.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Colhoun
authors.affiliation: Department of Clinical Sciences, Diabetes and Endocrinology, Skåne University Hospital, Lund University, Malmö, Sweden.
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
authors.affiliation: Wellcome Trust Centre for Human Genetics|Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom.|Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, United Kingdom.
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland|Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.|Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.|Baker IDI (International Diabetes Institute) Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Per-Henrik
authors.initials: PH
authors.lastname: Groop
mesh_terms: D000293:Adolescent; D000328:Adult; D003922:Diabetes Mellitus, Type 1 / Q000150:complications* / Q000235:genetics*; D003928:Diabetic Nephropathies / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D055815:Young Adult
keywords: diabetic kidney disease; genetics and development; genome-wide association study; whole exome sequencing