Genome-wide meta-analysis and omics integration identifies novel genes associated with diabetic kidney disease
Authors: Sandholm Niina , Cole Joanne B. , Nair Viji , Sheng Xin , Liu Hongbo , Ahlqvist Emma , van Zuydam Natalie , Dahlström Emma H. , Fermin Damian , Smyth Laura J. , Salem Rany M. , Forsblom Carol , Valo Erkka , Harjutsalo Valma , Brennan Eoin P. , McKay Gareth J. , Andrews Darrell , Doyle Ross , Looker Helen C. , Nelson Robert G. , Palmer Colin , McKnight Amy Jayne , Godson Catherine , Maxwell Alexander P. , Groop Leif , McCarthy Mark I. , Kretzler Matthias , Susztak Katalin , Hirschhorn Joel N. , Florez Jose C. , Groop Per-Henrik ,   for the GENIE Consortium
Published: June 2022

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).

Graphical abstract