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. 2022 Nov 23;10(12):3023.
doi: 10.3390/biomedicines10123023.

A Genome-Wide Association Study into the Aetiology of Congenital Solitary Functioning Kidney

Sander Groen In 't Woud  1   2 , Carlo Maj  3 , Kirsten Y Renkema  4 , Rik Westland  5 , Tessel Galesloot  1 , Iris A L M van Rooij  1 , Sita H Vermeulen  1 , Wout F J Feitz  6 , Nel Roeleveld  1 , Michiel F Schreuder  2 , Loes F M van der Zanden  1 ; SOFIA Study Group
Affiliations

A Genome-Wide Association Study into the Aetiology of Congenital Solitary Functioning Kidney

Sander Groen In 't Woud et al. Biomedicines. .

Abstract

Congenital solitary functioning kidney (CSFK) is a birth defect that occurs in 1:1500 children and predisposes them to kidney injury. Its aetiology is likely multifactorial. In addition to known monogenic causes and environmental risk factors, common genetic variation may contribute to susceptibility to CSFK. We performed a genome-wide association study among 452 patients with CSFK and two control groups of 669 healthy children and 5363 unaffected adults. Variants in two loci reached the genome-wide significance threshold of 5 × 10-8, and variants in 30 loci reached the suggestive significance threshold of 1 × 10-5. Of these, an identified locus with lead single nucleotide variant (SNV) rs140804918 (odds ratio 3.1, p-value = 1.4 × 10-8) on chromosome 7 was most promising due to its close proximity to HGF, a gene known to be involved in kidney development. Based on their known molecular functions, both KCTD20 and STK38 could explain the suggestive significant association with lead SNV rs148413365 on chromosome 6. Our findings need replication in an independent cohort of CSFK patients before they can be established definitively. However, our analysis suggests that common variants play a role in CSFK aetiology. Future research could enhance our understanding of the molecular mechanisms involved.

Keywords: aetiology; congenital anomalies of the kidney and urinary tract (CAKUT); genome-wide association study; kidney development; kidney hypodysplasia; multicystic dysplastic kidney; single nucleotide variant; solitary functioning kidney; unilateral kidney agenesis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Flowchart of the number of included patients and controls after recruitment, genotyping and quality control. GWAS: genome-wide association study; UKA: unilateral kidney agenesis; MCDK: multicystic dysplastic kidney; KHD: kidney hypo/dysplasia.
Figure 2
Figure 2
Quantile-quantile plot with lambda value for the AGORA dataset (403 patients and 622 controls).
Figure 3
Figure 3
Manhattan plot for the AGORA dataset (403 patients and 622 controls). The blue line indicates the threshold for suggestive statistical significance (p < 1 × 10−5).
Figure 4
Figure 4
Quantile-quantile plot with lambda value for the NBS dataset (403 patients and 4366 controls).
Figure 5
Figure 5
Manhattan plot for the NBS dataset (403 patients and 4366 controls). The blue line indicates the threshold for suggestive statistical significance (p-value < 1 × 10−5) and the red line indicates the threshold for genome-wide statistical significance (p-value < 5 × 10−8).
Figure 6
Figure 6
LocusZoom plots of: (A) SNV rs140804918 on chromosome 7. (B) SNV rs184382636 on chromosome 18. (C) SNV rs148413365 on chromosome 6. (D) SNV rs111283115 on chromosome 15.
Figure 7
Figure 7
LocusZoom plots for: (A) rs148251525. (B) rs10433490. (C) rs9547854. (D) rs2830456.
See this image and copyright information in PMC

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