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Genome-wide meta-an...
Genome-wide meta-analysis and omics integration identifies novel genes associated with diabetic kidney disease
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- Sandholm, Niina (author)
- University of Helsinki,Folkhälsan Research Center
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- Cole, Joanne B. (author)
- Broad Institute,Massachusetts General Hospital,Boston Children's Hospital
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Nair, Viji (author)
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- Sheng, Xin (author)
- University of Pennsylvania
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- Liu, Hongbo (author)
- University of Pennsylvania
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- Ahlqvist, Emma (author)
- Lund University,Lunds universitet,Translationell muskelforskning,Forskargrupper vid Lunds universitet,Translational Muscle Research,Lund University Research Groups,Skåne University Hospital
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- van Zuydam, Natalie (author)
- University of Dundee,University of Oxford
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- Dahlström, Emma H. (author)
- University of Helsinki,Folkhälsan Research Center
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Fermin, Damian (author)
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- Smyth, Laura J. (author)
- Queen's University Belfast
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- Salem, Rany M. (author)
- University of California, San Diego
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- Forsblom, Carol (author)
- University of Helsinki,Folkhälsan Research Center
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- Valo, Erkka (author)
- Folkhälsan Research Center,University of Helsinki
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- Harjutsalo, Valma (author)
- University of Helsinki,Folkhälsan Research Center
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- Brennan, Eoin P. (author)
- University College Dublin
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- McKay, Gareth J. (author)
- Queen's University Belfast
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- Andrews, Darrell (author)
- University College Dublin
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- Doyle, Ross (author)
- University College Dublin
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- Looker, Helen C. (author)
- National Institute of Diabetes and Digestive and Kidney Diseases
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- Nelson, Robert G. (author)
- National Institute of Diabetes and Digestive and Kidney Diseases
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- Palmer, Colin (author)
- University of Dundee
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- McKnight, Amy Jayne (author)
- Queen's University Belfast
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- Godson, Catherine (author)
- University College Dublin
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- Maxwell, Alexander P. (author)
- Queen's University Belfast
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- Groop, Leif (author)
- Lund University,Lunds universitet,Translationell muskelforskning,Forskargrupper vid Lunds universitet,Translational Muscle Research,Lund University Research Groups,Skåne University Hospital,University of Helsinki
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- McCarthy, Mark I. (author)
- University of Oxford
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Kretzler, Matthias (author)
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- Susztak, Katalin (author)
- University of Pennsylvania
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- Hirschhorn, Joel N. (author)
- Boston Children's Hospital,Broad Institute,Harvard Medical School
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- Florez, Jose C. (author)
- Harvard Medical School,Broad Institute,Massachusetts General Hospital
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- Groop, Per Henrik (author)
- Folkhälsan Research Center,Monash University,University of Helsinki
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(creator_code:org_t)
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- 2022-06-28
- 2022
- English 15 s.
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In: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 65:9, s. 1495-1509
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http://dx.doi.org/10... (free)
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https://lup.lub.lu.s...
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Abstract
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- Aims/hypothesis: Diabetic kidney disease (DKD) is the leading cause of kidney failure and has a substantial genetic component. Our aim was to identify novel genetic factors and genes contributing to DKD by performing meta-analysis of previous genome-wide association studies (GWAS) on DKD and by integrating the results with renal transcriptomics datasets. Methods: We performed GWAS meta-analyses using ten phenotypic definitions of DKD, including nearly 27,000 individuals with diabetes. Meta-analysis results were integrated with estimated quantitative trait locus data from human glomerular (N=119) and tubular (N=121) samples to perform transcriptome-wide association study. We also performed gene aggregate tests to jointly test all available common genetic markers within a gene, and combined the results with various kidney omics datasets. Results: The meta-analysis identified a novel intronic variant (rs72831309) in the TENM2 gene associated with a lower risk of the combined chronic kidney disease (eGFR<60 ml/min per 1.73 m2) and DKD (microalbuminuria or worse) phenotype (p=9.8×10−9; although not withstanding correction for multiple testing, p>9.3×10−9). Gene-level analysis identified ten genes associated with DKD (COL20A1, DCLK1, EIF4E, PTPRN–RESP18, GPR158, INIP–SNX30, LSM14A and MFF; p<2.7×10−6). Integration of GWAS with human glomerular and tubular expression data demonstrated higher tubular AKIRIN2 gene expression in individuals with vs without DKD (p=1.1×10−6). The lead SNPs within six loci significantly altered DNA methylation of a nearby CpG site in kidneys (p<1.5×10−11). Expression of lead genes in kidney tubules or glomeruli correlated with relevant pathological phenotypes (e.g. TENM2 expression correlated positively with eGFR [p=1.6×10−8] and negatively with tubulointerstitial fibrosis [p=2.0×10−9], tubular DCLK1 expression correlated positively with fibrosis [p=7.4×10−16], and SNX30 expression correlated positively with eGFR [p=5.8×10−14] and negatively with fibrosis [p<2.0×10−16]). Conclusions/interpretation: Altogether, the results point to novel genes contributing to the pathogenesis of DKD. Data availability: The GWAS meta-analysis results can be accessed via the type 1 and type 2 diabetes (T1D and T2D, respectively) and Common Metabolic Diseases (CMD) Knowledge Portals, and downloaded on their respective download pages (https://t1d.hugeamp.org/downloads.html; https://t2d.hugeamp.org/downloads.html; https://hugeamp.org/downloads.html). Graphical abstract: [Figure not available: see fulltext.]
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
Keyword
- Diabetes complications
- Diabetic kidney disease
- Genetics
- Genome-wide association study; Meta-analysis; Transcriptomics
Publication and Content Type
- art (subject category)
- ref (subject category)
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- By the author/editor
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Sandholm, Niina
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Cole, Joanne B.
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Nair, Viji
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Sheng, Xin
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Liu, Hongbo
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Ahlqvist, Emma
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show more...
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van Zuydam, Nata ...
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Dahlström, Emma ...
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Fermin, Damian
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Smyth, Laura J.
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Salem, Rany M.
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Forsblom, Carol
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Valo, Erkka
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Harjutsalo, Valm ...
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Brennan, Eoin P.
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McKay, Gareth J.
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Andrews, Darrell
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Doyle, Ross
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Looker, Helen C.
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Nelson, Robert G ...
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Palmer, Colin
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McKnight, Amy Ja ...
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Godson, Catherin ...
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Maxwell, Alexand ...
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Groop, Leif
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McCarthy, Mark I ...
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Kretzler, Matthi ...
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Susztak, Katalin
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Hirschhorn, Joel ...
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Florez, Jose C.
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Groop, Per Henri ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Medical Genetics
- Articles in the publication
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Diabetologia
- By the university
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Lund University