Genome-wide meta-analysis and omics integration identifies novel genes associated with diabetic kidney disease
Genome-wide meta-analysis and omics integration identifies novel genes associated with diabetic kidney disease
Abstract BackgroundDiabetes is the leading cause of kidney disease, and heritability studies demonstrate a substantial, yet poorly understood, contribution of genetics to kidney complications in people with diabetes. MethodsWe performed genome-wide association study (GWAS) meta-analyses using ten different phenotypic definitions of diabetic kidney disease (DKD), including nearly 27,000 individuals with diabetes, and integrated the results with various kidney omics datasets. ResultsThe meta-analysis identified a novel low frequency intronic variant (rs72831309) in the TENM2 gene encoding teneurin transmembrane protein 2 associated with a lower risk of the combined chronic kidney disease (CKD; eGFR<60 ml/min/1.73 m2) and DKD (microalbuminuria or worse) phenotype (“CKD-DKD”, odds ratio 2.08, p=9.8×10?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 data with human glomerular and tubular expression data in a transcriptome-wide association study demonstrated higher tubular AKIRIN2 gene expression in DKD versus non-DKD controls (p=1.1×10?6). The lead SNPs within the DCLK1, AKIRIN2, SNX30 and three other gene regions significantly alterated the methylation at this region in kidneys (p<2.2×10?11). Expression of target genes in kidney tubules or glomeruli correlated with relevant pathological phenotypes. For example, tubular TENM2 expression positively correlated with eGFR (p=2.3×10?9) and negatively with tubulointerstitial fibrosis (p=4.7×10?9), tubular DCLK1 expression positively correlated with fibrosis (p=1.6×10?12), and SNX30 level positively correlated with eGFR (p=7.6×10?13) and negatively with fibrosis (p<2×10?16). ConclusionsGWAS meta-analysis and integration with renal omics data points to novel genes contributing to pathogenesis of DKD.
Florez Jose C、Palmer Colin、Godson Catherine、Maxwell Alexander P、McCarthy Mark I、for the GENIE Consortium、Cole Joanne B、Forsblom Carol、Nair Viji、Smyth Laura J、Susztak Katalin、McKay Gareth、Harjutsalo Valma、Andrews Darrell、Salem Rany M、Liu Hongbo、Sheng Xin、Dahlstr?m Emma H、Ahlqvist Emma、Looker Helen C、Valo Erkka、Groop Leif、Hirschhorn Joel N、Brennan Eoin P、McKnight Amy Jayne、Kretzler Matthias、Nelson Robert G、van Zuydam Natalie、Groop Per-Henrik、Doyle Ross、Sandholm Niina、Fermin Damian
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard||Department of Genetics, Harvard Medical School||Department of Medicine, Harvard Medical School||Diabetes Unit and Center for Genomic Medicine, Massachusetts General HospitalPat Macpherson Center for Pharmacogenetics & Pharmacogenomics, Cardiovascular & Diabetes Medicine, School of Medicine, University of DundeeDiabetes Complications Research Centre, Conway Institute, School of Medicine, University College DublinMolecular Epidemiology Research Group, Centre for Public Health, Queen?ˉs University Belfast||Regional Nephrology Unit, Belfast City HospitalWellcome Center for Human Genetics, Nuffield Department of Medicine, University of Oxford||Oxford Center for Diabetes, Endocrinology & Metabolism, Radcliffe Department of Medicine, University of OxfordProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard||Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children?ˉs Hospital||Diabetes Unit and Center for Genomic Medicine, Massachusetts General HospitalFolkh?lsan Institute of Genetics, Folkh?lsan Research Center||Department of Nephrology, University of Helsinki and Helsinki University Hospital||Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of HelsinkiMichigan MedicineMolecular Epidemiology Research Group, Centre for Public Health, Queen?ˉs University BelfastRenal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine||Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine||Department of Genetics, University of Pennsylvania, Perelman School of MedicineMolecular Epidemiology Research Group, Centre for Public Health, Queen?ˉs University BelfastFolkh?lsan Institute of Genetics, Folkh?lsan Research Center||Department of Nephrology, University of Helsinki and Helsinki University Hospital||Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki||Finnish Institute for Health and WelfareDiabetes Complications Research Centre, Conway Institute, School of Medicine, University College DublinHerbert Wertheim School of Public Health and Human Longevity Science, University of California San DiegoRenal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine||Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine||Department of Genetics, University of Pennsylvania, Perelman School of MedicineRenal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine||Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine||Department of Genetics, University of Pennsylvania, Perelman School of MedicineFolkh?lsan Institute of Genetics, Folkh?lsan Research Center||Department of Nephrology, University of Helsinki and Helsinki University Hospital||Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of HelsinkiDepartment of Clinical Sciences, Lund University Diabetes Centre, Lund University and Sk?ne University HospitalChronic Kidney Disease Study, National Institute of Diabetes and Digestive and Kidney DiseasesFolkh?lsan Institute of Genetics, Folkh?lsan Research Center||Department of Nephrology, University of Helsinki and Helsinki University Hospital||Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of HelsinkiDepartment of Clinical Sciences, Lund University Diabetes Centre, Lund University and Sk?ne University HospitalProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard||Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children?ˉs Hospital||Department of Genetics, Harvard Medical SchoolDiabetes Complications Research Centre, Conway Institute, School of Medicine, University College DublinMolecular Epidemiology Research Group, Centre for Public Health, Queen?ˉs University BelfastMichigan MedicineChronic Kidney Disease Study, National Institute of Diabetes and Digestive and Kidney DiseasesPat Macpherson Center for Pharmacogenetics & Pharmacogenomics, Cardiovascular & Diabetes Medicine, School of Medicine, University of Dundee||Oxford Center for Diabetes, Endocrinology & Metabolism, Radcliffe Department of Medicine, University of Oxford||Wellcome Center for Human Genetics, Nuffield Department of Medicine, University of OxfordFolkh?lsan Institute of Genetics, Folkh?lsan Research Center||Department of Nephrology, University of Helsinki and Helsinki University Hospital||Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki||Department of Diabetes, Central Clinical School, Monash UniversityDiabetes Complications Research Centre, Conway Institute, School of Medicine, University College DublinFolkh?lsan Institute of Genetics, Folkh?lsan Research Center||Department of Nephrology, University of Helsinki and Helsinki University Hospital||Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of HelsinkiMichigan Medicine
基础医学医学研究方法内科学
Diabetic kidney diseasegenome-wide association studygeneticstranscriptomicsdiabetes complications
Florez Jose C,Palmer Colin,Godson Catherine,Maxwell Alexander P,McCarthy Mark I,for the GENIE Consortium,Cole Joanne B,Forsblom Carol,Nair Viji,Smyth Laura J,Susztak Katalin,McKay Gareth,Harjutsalo Valma,Andrews Darrell,Salem Rany M,Liu Hongbo,Sheng Xin,Dahlstr?m Emma H,Ahlqvist Emma,Looker Helen C,Valo Erkka,Groop Leif,Hirschhorn Joel N,Brennan Eoin P,McKnight Amy Jayne,Kretzler Matthias,Nelson Robert G,van Zuydam Natalie,Groop Per-Henrik,Doyle Ross,Sandholm Niina,Fermin Damian.Genome-wide meta-analysis and omics integration identifies novel genes associated with diabetic kidney disease[EB/OL].(2025-03-28)[2025-06-29].https://www.medrxiv.org/content/10.1101/2021.08.27.21262264.点此复制
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