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Whole-exome sequencing study identifies four novel gene loci associated with diabetic kidney disease.

ABSTRACT: Diabetic kidney disease (DKD) is recognized as an important public health challenge. However, its genomic mechanisms are poorly understood. To identify rare variants for DKD, we conducted a whole-exome sequencing (WES) study leveraging large cohorts well-phenotyped for chronic kidney disease and diabetes. Our two-stage WES study included 4372 European and African ancestry participants from the Chronic Renal Insufficiency Cohort and Atherosclerosis Risk in Communities studies (stage 1) and 11 487 multi-ancestry Trans-Omics for Precision Medicine participants (stage 2). Generalized linear mixed models, which accounted for genetic relatedness and adjusted for age, sex and ancestry, were used to test associations between single variants and DKD. Gene-based aggregate rare variant analyses were conducted using an optimized sequence kernel association test implemented within our mixed model framework. We identified four novel exome-wide significant DKD-related loci through initiating diabetes. In single-variant analyses, participants carrying a rare, in-frame insertion in the DIS3L2 gene (rs141560952) exhibited a 193-fold increased odds [95% confidence interval (CI): 33.6, 1105] of DKD compared with noncarriers (P = 3.59 × 10-9). Likewise, each copy of a low-frequency KRT6B splice-site variant (rs425827) conferred a 5.31-fold higher odds (95% CI: 3.06, 9.21) of DKD (P = 2.72 × 10-9). Aggregate gene-based analyses further identified ERAP2 (P = 4.03 × 10-8) and NPEPPS (P = 1.51 × 10-7), which are both expressed in the kidney and implicated in renin-angiotensin-aldosterone system modulated immune response. In the largest WES study of DKD, we identified novel rare variant loci attaining exome-wide significance. These findings provide new insights into the molecular mechanisms underlying DKD.

SUBMITTER: Pan Y

PROVIDER: S-EPMC9990994 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Whole-exome sequencing study identifies four novel gene loci associated with diabetic kidney disease.

Pan Yang Y Sun Xiao X Mi Xuenan X Huang Zhijie Z Hsu Yenchih Y Hixson James E JE Munzy Donna D Metcalf Ginger G Franceschini Nora N Tin Adrienne A Köttgen Anna A Francis Michael M Brody Jennifer A JA Kestenbaum Bryan B Sitlani Colleen M CM Mychaleckyj Josyf C JC Kramer Holly H Lange Leslie A LA Guo Xiuqing X Hwang Shih-Jen SJ Irvin Marguerite R MR Smith Jennifer A JA Yanek Lisa R LR Vaidya Dhananjay D Chen Yii-Der Ida YI Fornage Myriam M Lloyd-Jones Donald M DM Hou Lifang L Mathias Rasika A RA Mitchell Braxton D BD Peyser Patricia A PA Kardia Sharon L R SLR Arnett Donna K DK Correa Adolfo A Raffield Laura M LM Vasan Ramachandran S RS Cupple L Adrienne LA Levy Daniel D Kaplan Robert C RC North Kari E KE Rotter Jerome I JI Kooperberg Charles C Reiner Alexander P AP Psaty Bruce M BM Tracy Russell P RP Gibbs Richard A RA Morrison Alanna C AC Feldman Harold H Boerwinkle Eric E He Jiang J Kelly Tanika N TN

Human molecular genetics 20230301 6

Diabetic kidney disease (DKD) is recognized as an important public health challenge. However, its genomic mechanisms are poorly understood. To identify rare variants for DKD, we conducted a whole-exome sequencing (WES) study leveraging large cohorts well-phenotyped for chronic kidney disease and diabetes. Our two-stage WES study included 4372 European and African ancestry participants from the Chronic Renal Insufficiency Cohort and Atherosclerosis Risk in Communities studies (stage 1) and 11 487 ...[more]

PMID: 36444934

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Project description:Aims/hypothesisDiabetic kidney disease (DKD) is a severe diabetic complication that affects one third of individuals with type 1 diabetes. Although several genes and common variants have been shown to be associated with DKD, much of the predicted inheritance remains unexplained. Here, we performed next-generation sequencing to assess whether low-frequency variants, extending to a minor allele frequency (MAF) ≤10% (single or aggregated) contribute to the missing heritability in DKD.MethodsWe performed whole-exome sequencing (WES) of 498 individuals and whole-genome sequencing (WGS) of 599 individuals with type 1 diabetes. After quality control, next-generation sequencing data were available for a total of 1064 individuals, of whom 541 had developed either severe albuminuria or end-stage kidney disease, and 523 had retained normal albumin excretion despite a long duration of type 1 diabetes. Single-variant and gene-aggregate tests for protein-altering variants (PAV) and protein-truncating variants (PTV) were performed separately for WES and WGS data and combined in a meta-analysis. We also performed genome-wide aggregate analyses on genomic windows (sliding window), promoters and enhancers using the WGS dataset.ResultsIn the single-variant meta-analysis, no variant reached genome-wide significance, but a suggestively associated common THAP7 rs369250 variant (p=1.50 × 10-5, MAF=49%) was replicated in the FinnGen general population genome-wide association study (GWAS) data for chronic kidney disease and DKD phenotypes. The gene-aggregate meta-analysis provided suggestive evidence (p<4.0 × 10-4) at four genes for DKD, of which NAT16 (MAFPAV≤10%) and LTA (also known as TNFβ, MAFPAV≤5%) are replicated in the FinnGen general population GWAS data. The LTA rs2229092 C allele was associated with significantly lower TNFR1, TNFR2 and TNFR3 serum levels in a subset of FinnDiane participants. Of the intergenic regions suggestively associated with DKD, the enhancer on chromosome 18q12.3 (p=3.94 × 10-5, MAFvariants≤5%) showed interaction with the METTL4 gene; the lead variant was replicated, and predicted to alter binding of the MafB transcription factor.Conclusions/interpretationOur sequencing-based meta-analysis revealed multiple genes, variants and regulatory regions that were suggestively associated with DKD. However, as no variant or gene reached genome-wide significance, further studies are needed to validate the findings.

Project description:BackgroundGenetic association studies for gastroschisis have highlighted several candidate variants. However, genetic basis in gastroschisis from noninvestigated heritable factors could provide new insights into the human biology for this birth defect. We aim to identify novel gastroschisis susceptibility variants by employing whole exome sequencing (WES) in a Mexican family with recurrence of gastroschisis.MethodsWe employed WES in two affected half-sisters with gastroschisis, mother, and father of the proband. Additionally, functional bioinformatics analysis was based on SVS-PhoRank and Ensembl-Variant Effect Predictor. The latter assessed the potentially deleterious effects (high, moderate, low, or modifier impact) from exome variants based on SIFT, PolyPhen, dbNSFP, Condel, LoFtool, MaxEntScan, and BLOSUM62 algorithms. The analysis was based on the Human Genome annotation, GRCh37/hg19. Candidate genes were prioritized and manually curated based on significant phenotypic relevance (SVS-PhoRank) and functional properties (Ensembl-Variant Effect Predictor). Functional enrichment analysis was performed using ToppGene Suite, including a manual curation of significant Gene Ontology (GO) biological processes from functional similarity analysis of candidate genes.ResultsNo single gene-disrupting variant was identified. Instead, 428 heterozygous variations were identified for which SPATA17, PDE4DIP, CFAP65, ALPP, ZNF717, OR4C3, MAP2K3, TLR8, and UBE2NL were predicted as high impact in both cases, mother, and father of the proband. PLOD1, COL6A3, FGFRL1, HHIP, SGCD, RAPGEF1, PKD1, ZFHX3, BCAS3, EVPL, CEACAM5, and KLK14 were segregated among both cases and mother. Multiple interacting background modifiers may regulate gastroschisis susceptibility. These candidate genes highlight a role for development of blood vessel, circulatory system, muscle structure, epithelium, and epidermis, regulation of cell junction assembly, biological/cell adhesion, detection/response to endogenous stimulus, regulation of cytokine biosynthetic process, response to growth factor, postreplication repair/protein K63-linked ubiquitination, protein-containing complex assembly, and regulation of transcription DNA-templated.ConclusionConsidering the likely gene-disrupting prediction results and similar biological pattern of mechanisms, we propose a joint "multifactorial model" in gastroschisis pathogenesis.

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Whole-exome sequencing study identifies four novel gene loci associated with diabetic kidney disease.

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Whole-exome sequencing study identifies four novel gene loci associated with diabetic kidney disease.

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