Genome-wide meta-analysis and omics integration identifies novel genes associated with diabetic kidney disease

Niina Sandholm*, Joanne B Cole, Viji Nair, Xin Sheng, Hongbo Liu, Emma Ahlqvist, Natalie Van Zuydam, Emma H Dahlström, Damian Fermin, Laura Smyth, Rany M Salem, Carol Forsblom, Erkka Valo, Valma Harjutsalo, Eoin P Brennan, Gareth McKay, Darrell Andrews, Ross Doyle, Helen Looker, Robert NelsonColin Palmer, Amy Jayne McKnight, Catherine Godson, Peter Maxwell, Leif Groop, Mark McCarthy, Matthias Kretzler, Katalin Susztak, Joel N Hirschhorn, Jose C Florez, Per-Henrik Groop

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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Abstract

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).
Original languageEnglish
JournalDiabetologia
Early online date28 Jun 2022
Publication statusEarly online date - 28 Jun 2022

Keywords

  • kidney
  • diabetic
  • diabetes
  • GWAS
  • omic
  • multiomic

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