Genomic copy number variation association study in Caucasian patients with nonsyndromic cryptorchidism

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.

Perspective: A Neuro-Hormonal Systems Approach to Understanding the Complexity of Cryptorchidism Susceptibility

“…It is unclear if these defects are primary or secondary, genetic or environmental. Our genome-wide association study (GWAS) of cryptorchidism identified many suggestive signals, but none surpassed the genome-wide significance threshold ( 57 – 59 ), typical of a polygenic disorder. Pathway analysis of suggestive intragenic signals showed enrichment of genes encoding proteins involved in cytoskeletal functions, including known or predicted ARIPs.…”

Molecular genetics of hypospadias and cryptorchidism recent developments

“…In a recent work, Wang et al performed a genomic CNV association study in cryptorchid boys, and they were unable to find a significant association with undescended testis. Forty‐nine out of 373 genome‐wide significant gene/loci selected by a meta‐analysis presented with deletions.…”

Copy number variants of Ras/MAPK pathway genes in patients with isolated cryptorchidism

“…A recent report by Wang et al . () described a genome wide genotyping analysis performed in 800 non‐syndromic patients with cryptorchidism and 2688 controls, in an attempt to identify structural variations. To our knowledge, this is the most thorough CNV analysis of non‐syndromic patients with cryptorchidism, but no structural variations were detected.…”