Abstract
BackgroundCopy number variation (CNV) is a potential contributing factor to many genetic diseases. Here we investigated the potential association of CNV with nonsyndromic cryptorchidism, the most common male congenital genitourinary defect, in a Caucasian population.MethodsGenome wide genotyping were performed in 559 cases and 1772 controls (Group 1) using Illumina HumanHap550 v1, HumanHap550 v3 or Human610-Quad platforms and in 353 cases and 1149 controls (Group 2) using the Illumina Human OmniExpress 12v1 or Human OmniExpress 12v1-1. Signal intensity data including log R ratio (LRR) and B allele frequency (BAF) for each single nucleotide polymorphism (SNP) were used for CNV detection using PennCNV software. After sample quality control, gene- and CNV-based association tests were performed using cleaned data from Group 1 (493 cases and 1586 controls) and Group 2 (307 cases and 1102 controls) using ParseCNV software. Meta-analysis was performed using gene-based test results as input to identify significant genes, and CNVs in or around significant genes were identified in CNV-based association test results. Called CNVs passing quality control and signal intensity visualization examination were considered for validation using TaqMan CNV assays and QuantStudio® 3D Digital PCR System.ResultsThe meta-analysis identified 373 genome wide significant (p < 5X10−4) genes/loci including 49 genes/loci with deletions and 324 with duplications. Among them, 17 genes with deletion and 1 gene with duplication were identified in CNV-based association results in both Group 1 and Group 2. Only 2 genes (NUCB2 and UPF2) containing deletions passed CNV quality control in both groups and signal intensity visualization examination, but laboratory validation failed to verify these deletions.ConclusionsOur data do not support that structural variation is a major cause of nonsyndromic cryptorchidism.Electronic supplementary materialThe online version of this article (doi:10.1186/s12894-016-0180-4) contains supplementary material, which is available to authorized users.
Highlights
Copy number variation (CNV) is a potential contributing factor to many genetic diseases
The direction of effect was inconsistent for 6 duplications and no direction was given in one duplication which was due to p = 1 for that gene in gene-based association test of Group 2, and they were removed from further consideration, leaving 324 genes/loci with duplication
We performed genome-wide CNV association analysis to identify the potential association of structural variation with the occurrence of nonsyndromic cryptorchidism, and our results suggest that CNVs do not contribute to the genetic basis of the nonsyndromic form of the disease
Summary
Copy number variation (CNV) is a potential contributing factor to many genetic diseases. We investigated the potential association of CNV with nonsyndromic cryptorchidism, the most common male congenital genitourinary defect, in a Caucasian population. Nonsyndromic cryptorchidism, or isolated undescended testis, is one of the most common pediatric congenital anomalies, affecting 2-3 % of boys, and is associated with infertility and testicular malignancy later in life [1]. Familial clustering suggests moderate genetic contribution to the disease [2]. We performed a genome-wide association study (GWAS) in 912 nonsyndromic cryptorchidism cases and 2921 controls [11, 12] to identify common allelic variants across the genome associated with the disease. Pathway analysis of suggestive association markers (p ≤ 10−3) using several bioinformatics tools identified overrepresentation of genes/functions linked to cytoskeleton-dependent processes, syndromic cryptorchidism and hypogonadotropic hypogonadism
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