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Genome-wide meta-an...
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Sandholm, NiinaUniversity of Helsinki,Folkhälsan Research Center
(author)
Genome-wide meta-analysis and omics integration identifies novel genes associated with diabetic kidney disease
- Article/chapterEnglish2022
Publisher, publication year, extent ...
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2022-06-28
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Springer Science and Business Media LLC,2022
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15 s.
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LIBRIS-ID:oai:lup.lub.lu.se:5214de8d-b236-439a-ae0d-c539fa8eb6a2
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https://lup.lub.lu.se/record/5214de8d-b236-439a-ae0d-c539fa8eb6a2URI
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https://doi.org/10.1007/s00125-022-05735-0DOI
Supplementary language notes
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Language:English
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Summary in:English
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Subject category:art swepub-publicationtype
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Subject category:ref swepub-contenttype
Notes
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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 and genre
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Cole, Joanne B.Massachusetts General Hospital,Broad Institute,Boston Children's Hospital
(author)
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Nair, Viji
(author)
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Sheng, XinUniversity of Pennsylvania
(author)
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Liu, HongboUniversity of Pennsylvania
(author)
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Ahlqvist, EmmaLund University,Lunds universitet,Translationell muskelforskning,Forskargrupper vid Lunds universitet,Translational Muscle Research,Lund University Research Groups,Skåne University Hospital(Swepub:lu)infl-eah
(author)
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van Zuydam, NatalieUniversity of Oxford,University of Dundee
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Dahlström, Emma H.Folkhälsan Research Center,University of Helsinki
(author)
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Fermin, Damian
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Smyth, Laura J.Queen's University Belfast
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Salem, Rany M.University of California, San Diego
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Forsblom, CarolUniversity of Helsinki,Folkhälsan Research Center
(author)
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Valo, ErkkaUniversity of Helsinki,Folkhälsan Research Center
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Harjutsalo, ValmaFolkhälsan Research Center,University of Helsinki
(author)
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Brennan, Eoin P.University College Dublin
(author)
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McKay, Gareth J.Queen's University Belfast
(author)
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Andrews, DarrellUniversity College Dublin
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Doyle, RossUniversity College Dublin
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Looker, Helen C.National Institute of Diabetes and Digestive and Kidney Diseases
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Nelson, Robert G.National Institute of Diabetes and Digestive and Kidney Diseases
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Palmer, ColinUniversity of Dundee
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McKnight, Amy JayneQueen's University Belfast
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Godson, CatherineUniversity College Dublin
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Maxwell, Alexander P.Queen's University Belfast
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Groop, LeifLund University,Lunds universitet,Translationell muskelforskning,Forskargrupper vid Lunds universitet,Translational Muscle Research,Lund University Research Groups,Skåne University Hospital,University of Helsinki(Swepub:lu)endo-lgr
(author)
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McCarthy, Mark I.University of Oxford
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Kretzler, Matthias
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Susztak, KatalinUniversity of Pennsylvania
(author)
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Hirschhorn, Joel N.Harvard Medical School,Broad Institute,Boston Children's Hospital
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Florez, Jose C.Harvard Medical School,Broad Institute,Massachusetts General Hospital
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Groop, Per HenrikMonash University,Folkhälsan Research Center,University of Helsinki
(author)
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University of HelsinkiFolkhälsan Research Center
(creator_code:org_t)
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GENIE (Genetics of Nepropathy an International Effort) Consortium
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In:Diabetologia: Springer Science and Business Media LLC65:9, s. 1495-15090012-186X1432-0428
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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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van Zuydam, Nata ...
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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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