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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 ...

  • 2022-06-28
  • Springer Science and Business Media LLC,2022
  • 15 s.

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  • LIBRIS-ID:oai:lup.lub.lu.se:5214de8d-b236-439a-ae0d-c539fa8eb6a2
  • https://lup.lub.lu.se/record/5214de8d-b236-439a-ae0d-c539fa8eb6a2URI
  • https://doi.org/10.1007/s00125-022-05735-0DOI

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  • Language:English
  • Summary in:English

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  • Subject category:art swepub-publicationtype
  • Subject category:ref swepub-contenttype

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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.]

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  • Cole, Joanne B.Massachusetts General Hospital,Broad Institute,Boston Children's Hospital (author)
  • Nair, Viji (author)
  • Sheng, XinUniversity of Pennsylvania (author)
  • Liu, HongboUniversity of Pennsylvania (author)
  • 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)
  • van Zuydam, NatalieUniversity of Oxford,University of Dundee (author)
  • Dahlström, Emma H.Folkhälsan Research Center,University of Helsinki (author)
  • Fermin, Damian (author)
  • Smyth, Laura J.Queen's University Belfast (author)
  • Salem, Rany M.University of California, San Diego (author)
  • Forsblom, CarolUniversity of Helsinki,Folkhälsan Research Center (author)
  • Valo, ErkkaUniversity of Helsinki,Folkhälsan Research Center (author)
  • Harjutsalo, ValmaFolkhälsan Research Center,University of Helsinki (author)
  • Brennan, Eoin P.University College Dublin (author)
  • McKay, Gareth J.Queen's University Belfast (author)
  • Andrews, DarrellUniversity College Dublin (author)
  • Doyle, RossUniversity College Dublin (author)
  • Looker, Helen C.National Institute of Diabetes and Digestive and Kidney Diseases (author)
  • Nelson, Robert G.National Institute of Diabetes and Digestive and Kidney Diseases (author)
  • Palmer, ColinUniversity of Dundee (author)
  • McKnight, Amy JayneQueen's University Belfast (author)
  • Godson, CatherineUniversity College Dublin (author)
  • Maxwell, Alexander P.Queen's University Belfast (author)
  • 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)
  • McCarthy, Mark I.University of Oxford (author)
  • Kretzler, Matthias (author)
  • Susztak, KatalinUniversity of Pennsylvania (author)
  • Hirschhorn, Joel N.Harvard Medical School,Broad Institute,Boston Children's Hospital (author)
  • Florez, Jose C.Harvard Medical School,Broad Institute,Massachusetts General Hospital (author)
  • Groop, Per HenrikMonash University,Folkhälsan Research Center,University of Helsinki (author)
  • University of HelsinkiFolkhälsan Research Center (creator_code:org_t)
  • GENIE (Genetics of Nepropathy an International Effort) Consortium

Related titles

  • In:Diabetologia: Springer Science and Business Media LLC65:9, s. 1495-15090012-186X1432-0428

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