The genetic landscape of renal complications in type 1 diabetes

Niina Sandholm, Natalie Van Zuydam, Emma Ahlqvist, Thorhildur Juliusdottir, Harshal A. Deshmukh, N. William Rayner, Barbara Di Camillo, Carol Forsblom, Joao Fadista, Daniel Ziemek, Rany M. Salem, Linda T. Hiraki, Marcus Pezzolesi, David Trégouët, Emma Dahlström, Erkka Valo, Nikolay Oskolkov, Claes Ladenvall, M. Loredana Marcovecchio, Jason Cooper & 31 others Francesco Sambo, Alberto Malovini, Marco Manfrini, Amy Jayne McKnight, Maria Lajer, Valma Harjutsalo, Daniel Gordin, Maija Parkkonen, The FinnDiane Study Group, Jaakko Tuomilehto, Valeriya Lyssenko, Paul M. McKeigue, Stephen S. Rich, Mary Julia Brosnan, Eric Fauman, Riccardo Bellazzi, Peter Rossing, Andrzej Krolewski, Andrew D. Paterson, The DCCT/EDIC Study Group, Jose C. Florez, Joel N. Hirschhorn, Alexander P. Maxwell, GENIE Consortium, David Dunger, Claudio Cobelli, Helen M. Colhoun, Leif Groop, Mark I. McCarthy, Per-Henrik Groop, SUMMIT Consortium

    Research output: Contribution to journalArticle

    30 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)557-574
    Number of pages18
    JournalJournal of the American Society of Nephrology
    Volume28
    Issue number2
    Early online date19 Sep 2016
    DOIs
    Publication statusPublished - Feb 2017

    Fingerprint

    Diabetic Nephropathies
    Type 1 Diabetes Mellitus
    Kidney
    Exome
    Pentoses
    Glucuronic Acid
    Genome-Wide Association Study
    Kidney Diseases
    Smoking Cessation
    Genetic Predisposition to Disease
    Gene Frequency
    Type 2 Diabetes Mellitus
    Chronic Kidney Failure
    Renal Insufficiency
    Body Mass Index
    Alleles
    Genome
    Phenotype

    Cite this

    Sandholm, N., Van Zuydam, N., Ahlqvist, E., Juliusdottir, T., Deshmukh, H. A., Rayner, N. W., ... SUMMIT Consortium (2017). The genetic landscape of renal complications in type 1 diabetes. Journal of the American Society of Nephrology, 28(2), 557-574. https://doi.org/10.1681/ASN.2016020231
    Sandholm, Niina ; Van Zuydam, Natalie ; Ahlqvist, Emma ; Juliusdottir, Thorhildur ; Deshmukh, Harshal A. ; Rayner, N. William ; Di Camillo, Barbara ; Forsblom, Carol ; Fadista, Joao ; Ziemek, Daniel ; Salem, Rany M. ; Hiraki, Linda T. ; Pezzolesi, Marcus ; Trégouët, David ; Dahlström, Emma ; Valo, Erkka ; Oskolkov, Nikolay ; Ladenvall, Claes ; Marcovecchio, M. Loredana ; Cooper, Jason ; Sambo, Francesco ; Malovini, Alberto ; Manfrini, Marco ; McKnight, Amy Jayne ; Lajer, Maria ; Harjutsalo, Valma ; Gordin, Daniel ; Parkkonen, Maija ; The FinnDiane Study Group ; Tuomilehto, Jaakko ; Lyssenko, Valeriya ; McKeigue, Paul M. ; Rich, Stephen S. ; Brosnan, Mary Julia ; Fauman, Eric ; Bellazzi, Riccardo ; Rossing, Peter ; Krolewski, Andrzej ; Paterson, Andrew D. ; The DCCT/EDIC Study Group ; Florez, Jose C. ; Hirschhorn, Joel N. ; Maxwell, Alexander P. ; GENIE Consortium ; Dunger, David ; Cobelli, Claudio ; Colhoun, Helen M. ; Groop, Leif ; McCarthy, Mark I. ; Groop, Per-Henrik ; SUMMIT Consortium. / The genetic landscape of renal complications in type 1 diabetes. In: Journal of the American Society of Nephrology. 2017 ; Vol. 28, No. 2. pp. 557-574.
    @article{43b1348b7cc94569986a4e14b42f0e3d,
    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.",
    author = "Niina Sandholm and {Van Zuydam}, Natalie and Emma Ahlqvist and Thorhildur Juliusdottir and Deshmukh, {Harshal A.} and Rayner, {N. William} and {Di Camillo}, Barbara and Carol Forsblom and Joao Fadista and Daniel Ziemek and Salem, {Rany M.} and Hiraki, {Linda T.} and Marcus Pezzolesi and David Tr{\'e}gou{\"e}t and Emma Dahlstr{\"o}m and Erkka Valo and Nikolay Oskolkov and Claes Ladenvall and Marcovecchio, {M. Loredana} and Jason Cooper and Francesco Sambo and Alberto Malovini and Marco Manfrini and McKnight, {Amy Jayne} and Maria Lajer and Valma Harjutsalo and Daniel Gordin and Maija Parkkonen and {The FinnDiane Study Group} and Jaakko Tuomilehto and Valeriya Lyssenko and McKeigue, {Paul M.} and Rich, {Stephen S.} and Brosnan, {Mary Julia} and Eric Fauman and Riccardo Bellazzi and Peter Rossing and Samy Hadjadj and Andrzej Krolewski and Paterson, {Andrew D.} and {The DCCT/EDIC Study Group} and Florez, {Jose C.} and Hirschhorn, {Joel N.} and Maxwell, {Alexander P.} and {GENIE Consortium} and David Dunger and Claudio Cobelli and Colhoun, {Helen M.} and Leif Groop and McCarthy, {Mark I.} and Per-Henrik Groop and {SUMMIT Consortium}",
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    language = "English",
    volume = "28",
    pages = "557--574",
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    Sandholm, N, Van Zuydam, N, Ahlqvist, E, Juliusdottir, T, Deshmukh, HA, Rayner, NW, Di Camillo, B, Forsblom, C, Fadista, J, Ziemek, D, Salem, RM, Hiraki, LT, Pezzolesi, M, Trégouët, D, Dahlström, E, Valo, E, Oskolkov, N, Ladenvall, C, Marcovecchio, ML, Cooper, J, Sambo, F, Malovini, A, Manfrini, M, McKnight, AJ, Lajer, M, Harjutsalo, V, Gordin, D, Parkkonen, M, The FinnDiane Study Group, Tuomilehto, J, Lyssenko, V, McKeigue, PM, Rich, SS, Brosnan, MJ, Fauman, E, Bellazzi, R, Rossing, P, Krolewski, A, Paterson, AD, The DCCT/EDIC Study Group, Florez, JC, Hirschhorn, JN, Maxwell, AP, GENIE Consortium, Dunger, D, Cobelli, C, Colhoun, HM, Groop, L, McCarthy, MI, Groop, P-H & SUMMIT Consortium 2017, 'The genetic landscape of renal complications in type 1 diabetes', Journal of the American Society of Nephrology, vol. 28, no. 2, pp. 557-574. https://doi.org/10.1681/ASN.2016020231

    The genetic landscape of renal complications in type 1 diabetes. / Sandholm, Niina; Van Zuydam, Natalie; Ahlqvist, Emma; Juliusdottir, Thorhildur; Deshmukh, Harshal A.; Rayner, N. William; Di Camillo, Barbara; Forsblom, Carol; Fadista, Joao; Ziemek, Daniel; Salem, Rany M.; Hiraki, Linda T.; Pezzolesi, Marcus; Trégouët, David; Dahlström, Emma; Valo, Erkka; Oskolkov, Nikolay; Ladenvall, Claes; Marcovecchio, M. Loredana; Cooper, Jason; Sambo, Francesco; Malovini, Alberto; Manfrini, Marco; McKnight, Amy Jayne; Lajer, Maria; Harjutsalo, Valma; Gordin, Daniel; Parkkonen, Maija; The FinnDiane Study Group; Tuomilehto, Jaakko; Lyssenko, Valeriya; McKeigue, Paul M.; Rich, Stephen S.; Brosnan, Mary Julia; Fauman, Eric; Bellazzi, Riccardo; Rossing, Peter; Krolewski, Andrzej; Paterson, Andrew D.; The DCCT/EDIC Study Group; Florez, Jose C.; Hirschhorn, Joel N.; Maxwell, Alexander P.; GENIE Consortium; Dunger, David; Cobelli, Claudio; Colhoun, Helen M.; Groop, Leif; McCarthy, Mark I.; Groop, Per-Henrik (Lead / Corresponding author); SUMMIT Consortium.

    In: Journal of the American Society of Nephrology, Vol. 28, No. 2, 02.2017, p. 557-574.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - The genetic landscape of renal complications in type 1 diabetes

    AU - Sandholm, Niina

    AU - Van Zuydam, Natalie

    AU - Ahlqvist, Emma

    AU - Juliusdottir, Thorhildur

    AU - Deshmukh, Harshal A.

    AU - Rayner, N. William

    AU - Di Camillo, Barbara

    AU - Forsblom, Carol

    AU - Fadista, Joao

    AU - Ziemek, Daniel

    AU - Salem, Rany M.

    AU - Hiraki, Linda T.

    AU - Pezzolesi, Marcus

    AU - Trégouët, David

    AU - Dahlström, Emma

    AU - Valo, Erkka

    AU - Oskolkov, Nikolay

    AU - Ladenvall, Claes

    AU - Marcovecchio, M. Loredana

    AU - Cooper, Jason

    AU - Sambo, Francesco

    AU - Malovini, Alberto

    AU - Manfrini, Marco

    AU - McKnight, Amy Jayne

    AU - Lajer, Maria

    AU - Harjutsalo, Valma

    AU - Gordin, Daniel

    AU - Parkkonen, Maija

    AU - The FinnDiane Study Group

    AU - Tuomilehto, Jaakko

    AU - Lyssenko, Valeriya

    AU - McKeigue, Paul M.

    AU - Rich, Stephen S.

    AU - Brosnan, Mary Julia

    AU - Fauman, Eric

    AU - Bellazzi, Riccardo

    AU - Rossing, Peter

    AU - Hadjadj, Samy

    AU - Krolewski, Andrzej

    AU - Paterson, Andrew D.

    AU - The DCCT/EDIC Study Group

    AU - Florez, Jose C.

    AU - Hirschhorn, Joel N.

    AU - Maxwell, Alexander P.

    AU - GENIE Consortium

    AU - Dunger, David

    AU - Cobelli, Claudio

    AU - Colhoun, Helen M.

    AU - Groop, Leif

    AU - McCarthy, Mark I.

    AU - Groop, Per-Henrik

    AU - SUMMIT Consortium

    N1 - Copyright © 2016 by the American Society of Nephrology.

    PY - 2017/2

    Y1 - 2017/2

    N2 - 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.

    AB - 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.

    U2 - 10.1681/ASN.2016020231

    DO - 10.1681/ASN.2016020231

    M3 - Article

    VL - 28

    SP - 557

    EP - 574

    JO - Journal of the American Society of Nephrology

    JF - Journal of the American Society of Nephrology

    SN - 1046-6673

    IS - 2

    ER -

    Sandholm N, Van Zuydam N, Ahlqvist E, Juliusdottir T, Deshmukh HA, Rayner NW et al. The genetic landscape of renal complications in type 1 diabetes. Journal of the American Society of Nephrology. 2017 Feb;28(2):557-574. https://doi.org/10.1681/ASN.2016020231