Association Of Copy Number Variations Research Articles

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

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.

Genome-wide association study of copy number variation with lung function identifies a novel signal of association near BANP for forced vital capacity.

BackgroundGenome-wide association studies of Single Nucleotide Polymorphisms (SNPs) have identified 55 SNPs associated with lung function. However, little is known about the effect of copy number variants (CNVs) on lung function, although CNVs represent a significant proportion of human genetic polymorphism. To assess the effect of CNVs on lung function quantitative traits, we measured copy number at 2788 previously characterised, common copy number variable regions in 6 independent cohorts (n = 24,237) using intensity data from SNP genotyping experiments. We developed a pipeline for genome-wide association analysis and meta-analysis of CNV genotypes measured across multiple studies using SNP genotype array intensity data from different platform technologies. We then undertook cohort-level genome-wide association studies of CNV with lung function in a subset of 4 cohorts (n < =12,403) with lung function measurements and meta-analysed the results. Follow-up was undertaken for CNVs which were well tagged by SNPs, in up to 146,871 individuals.ResultsWe generated robust copy number calls for 1962 out of 2788 (70 %) known CNV regions genome-wide, with 1103 measured with compatible class frequencies in at least 2 cohorts. We report a novel CNV association (discovery P = 0.0007) with Forced Vital Capacity (FVC) downstream of BANP on chromosome 16 that shows evidence of replication by a tag SNP in two independent studies (replication P = 0.004). In addition, we provide suggestive evidence (discovery P = 0.0002) for a role of complex copy number variation at a previously reported lung function locus, containing the rootletin gene CROCC, that is not tagged by SNPs.ConclusionsWe demonstrate how common CNV regions can be reliably and consistently called across cohorts, using an existing calling algorithm and rigorous quality control steps, using SNP genotyping array intensity data. Although many common biallelic CNV regions were well-tagged by common SNPs, we also identified associations with untagged mulitallelic CNV regions thereby illustrating the potential of our approach to identify some of the missing heritability of complex traits.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-016-0423-0) contains supplementary material, which is available to authorized users.

Copy number variations in 375 patients with oesophageal atresia and/or tracheoesophageal fistula.

Oesophageal atresia (OA) with or without tracheoesophageal fistula (TOF) are rare anatomical congenital malformations whose cause is unknown in over 90% of patients. A genetic background is suggested, and among the reported genetic defects are copy number variations (CNVs). We hypothesized that CNVs contribute to OA/TOF development. Quantifying their prevalence could aid in genetic diagnosis and clinical care strategies. Therefore, we profiled 375 patients in a combined Dutch, American and German cohort via genomic microarray and compared the CNV profiles with their unaffected parents and published control cohorts. We identified 167 rare CNVs containing genes (frequency<0.0005 in our in-house cohort). Eight rare CNVs - in six patients - were de novo, including one CNV previously associated with oesophageal disease. (hg19 chr7:g.(143820444_143839360)_(159119486_159138663)del) 1.55% of isolated OA/TOF patients and 1.62% of patients with additional congenital anomalies had de novo CNVs. Furthermore, three (15q13.3, 16p13.3 and 22q11.2) susceptibility loci were identified based on their overlap with known OA/TOF-associated CNV syndromes and overlap with loci in published CNV association case-control studies in developmental delay. Our study suggests that CNVs contribute to OA/TOF development. In addition to the identified likely deleterious de novo CNVs, we detected 167 rare CNVs. Although not directly disease-causing, these CNVs might be of interest, as they can act as a modifier in a multiple hit model, or as the second hit in a recessive condition.

New quality measure for SNP array based CNV detection.

Only a few large systematic studies have evaluated the impact of copy number variants (CNVs) on common diseases. Several million individuals have been genotyped on single nucleotide variation arrays, which could be used for genome-wide CNVs association studies. However, CNV calls remain prone to false positives and only empirical filtering strategies exist in the literature. To overcome this issue, we defined a new quality score (QS) estimating the probability of a CNV called by PennCNV to be confirmed by other software. Out-of-sample comparison showed that the correlation between the consensus CNV status and the QS is twice as high as it is for any previously proposed CNV filters. ROC curves displayed an AUC higher than 0.8 and simulations showed an increase up to 20% in statistical power when using QS in comparison to other filtering strategies. Superior performance was confirmed also for alternative consensus CNV definition and through improving known CNV-trait associations. http://goo.gl/T6yuFM CONTACT: zoltan.kutalik@unil.ch or aurelien@mace@unil.chSupplementary information: Supplementary data are available at Bioinformatics online.

Genome-wide patterns of copy number variation in the Chinese yak genome.

BackgroundCopy number variation (CNV) represents an important source of genetic divergence that can produce drastic phenotypic differences and may therefore be subject to selection during domestication and environmental adaptation. To investigate the evolutionary dynamics of CNV in the yak genome, we used a read depth approach to detect CNV based on genome resequencing data from 14 wild and 65 domestic yaks and determined CNV regions related to domestication and adaptations to high-altitude.ResultsWe identified 2,634 CNV regions (CNVRs) comprising a total of 153 megabases (5.7 % of the yak genome) and 3,879 overlapping annotated genes. Comparison between domestic and wild yak populations identified 121 potentially selected CNVRs, harboring genes related to neuronal development, reproduction, nutrition and energy metabolism. In addition, we found 85 CNVRs that are significantly different between domestic yak living in high- and low-altitude areas, including three genes related to hypoxia response and six related to immune defense. This analysis shows that genic CNVs may play an important role in phenotypic changes during yak domestication and adaptation to life at high-altitude.ConclusionsWe present the first refined CNV map for yak along with comprehensive genomic analysis of yak CNV. Our results provide new insights into the genetic basis of yak domestication and adaptation to living in a high-altitude environment, as well as a valuable genetic resource that will facilitate future CNV association studies of important traits in yak and other bovid species.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2702-6) contains supplementary material, which is available to authorized users.

Gender differences in CNV burden do not confound schizophrenia CNV associations.

Compared with the general population, an excess of rare copy number variants (CNVs) has been identified in people with schizophrenia. Females with neurodevelopmental disorders and in the general population have been reported to carry more large, rare CNVs than males. Given that many schizophrenia datasets do not have equal gender ratios in cases and controls, sex differences in CNV burden might have impacted on estimates of case-related CNV burden and also on associations to individual loci. In a sample of 13,276 cases and 17,863 controls, we observed a small but significant excess of large (≥500 Kb), rare (<1%) CNVs in females compared with males in both cases and controls (OR = 1.17, P = 0.0012 for controls; OR = 1.11, P = 0.045 for cases). The burden of 11 schizophrenia-associated CNVs was significantly higher in female cases compared with male cases (OR = 1.38, P = 0.0055), but after accounting for the rates of CNVs in controls, we found no significant gender difference in the risk conferred by these loci. Controlling for gender had a negligible effect on the significance of association between specific CNVs and schizophrenia. The female excess of large CNVs in both cases and controls suggests a female protective mechanism exists for deleterious CNVs that may extend beyond neurodevelopmental phenotypes.

Analysis copy number variation of Chinese children in early-onset epileptic encephalopathies with unknown cause.

Copy number variations (CNVs) play an important role in the genetic etiology of unknown cause early-onset epileptic encephalopathies (EOEEs), but the genomic CNVs analysis of Chinese EOEEs children was rare. Here, we identified CNVs by single nucleotide polymorphism array in 116 patients with different subtypes of EOEEs. Of 116 patients 17 (14.66%) carried 19 large CNVs. A total of 14 CNVs in 12 patients were further validated: four of the CNVs were classified as de novo, seven were maternal, and three were paternal. Follow-up of those 12 patients showed that 5 had been seizure-free for at least 9 months, 5 had seizures several times per month or per year, and 2 had seizures everyday. But eight patients have profound developmental delay. In this study, we found at least 3.4% of patients had pathogenic CNVs. For the patients, our study laid the foundation for prenatal interventions for their families. Further, we identified potential candidate gene involved in EOEEs. The association of CNVs and clinical features will contribute to the understanding of EOEEs.

A genome-wide association study of copy number variations with umbilical hernia in swine.

Umbilical hernia (UH) is one of the most common congenital defects in pigs, leading to considerable economic loss and serious animal welfare problems. To test whether copy number variations (CNVs) contribute to pig UH, we performed a case-control genome-wide CNV association study on 905 pigs from the Duroc, Landrace and Yorkshire breeds using the Porcine SNP60 BeadChip and penncnv algorithm. We first constructed a genomic map comprising 6193 CNVs that pertain to 737 CNV regions. Then, we identified eight CNVs significantly associated with the risk for UH in the three pig breeds. Six of seven significantly associated CNVs were validated using quantitative real-time PCR. Notably, a rare CNV (CNV14:13030843-13059455) encompassing the NUGGC gene was strongly associated with UH (permutation-corrected P=0.0015) in Duroc pigs. This CNV occurred exclusively in seven Duroc UH-affected individuals. SNPs surrounding the CNV did not show association signals, indicating that rare CNVs may play an important role in complex pig diseases such as UH. The NUGGC gene has been implicated in human omphalocele and inguinal hernia. Our finding supports that CNVs, including the NUGGC CNV, contribute to the pathogenesis of pig UH.

Association of copy number variation of exon 11 of IL-23 receptor gene with susceptibility to tuberculosis among Chinese Uygurs

To assess the association of copy number variations (CNVs) of exon 11 of IL-23 receptor gene with susceptibility to active pulmonary tuberculosis among Chinese Uygurs. In this study, 250 subjects with active pulmonary tuberculosis (PTB) and 250 normal controls were recruited. A paired case-control study was conducted in the Chinese Uygur population in Xinjiang and the CNV of IL-23R was analyzed using Taqman real-time PCR. The study showed that the frequencies of different copy number in exon 11 of IL-23R between PTB and control groups were statistically significant (χ(2)=13.35, P<0.01). There were significant difference in CNV of exon 11 in IL-23R between PTB patients and controls (χ(2)=14.95, P<0.01, OR=2.875, 95%CI: 1.655-4.994). The increase of copy number in exon 11 of IL-23R showed significantly different between PTB and control groups (χ(2)=10.475, P=0.0012, OR=2.611, 95%CI: 1.437-4.744). The CNV of exon 11 in IL-23R is associated with PTB in the Chinese Uygur population. The increase of the copy number in exon 11 of IL-23R may be a risk factor for PTB in Chinese Uygurs.

MiR-23a, miR-146a and miR-301a confer predisposition to Vogt-Koyanagi-Harada syndrome but not to Behcet's disease.

Ninety-eight miRNAs are involved in the immune response. However, the genetic roles of these miRNAs remain unclear in Behcet’s disease (BD) and Vogt-Koyanagi-Harada (VKH) syndrome. This study aimed to explore the association and functional roles of copy number variants (CNV) in several miRNAs with BD and VKH syndrome. Genotyping of CNVs was examined by TaqMan PCR. The expression of miR-23a, transfection efficiency and cytokine production were measured by real-time PCR, flow cytometry or ELISA. First, replication and combined studies for miR-23a, miR-146a and miR-301a demonstrated a similar association with VKH syndrome (Combined: P = 5.53 × 10−8; P = 8.43 × 10−31; P = 9.23 × 10−8, respectively). No association of CNVs of the above mentioned miRNAs was observed in BD patients. mRNA expression of miR-23a showed a positive association with its copy numbers. Additionally, individuals with high copy number of miR-23a show an increased production of interleukin-6 (IL-6), but not IL-8 and monocyte chemoattractant protein-1 (MCP-1) by stimulated PBMCs. miR-23a transfected ARPE-19 cells modulated the production of IL-6 and IL-8, but not MCP-1. Our results suggest that CNVs of miR-146a, miR-23a and miR-301a confer susceptibility to VKH syndrome, but not to BD. The contribution of miR-23a to VKH syndrome may be mediated by increasing the production of IL-6.

Genome Reduction Uncovers a Large Dispensable Genome and Adaptive Role for Copy Number Variation in Asexually Propagated Solanum tuberosum.

Clonally reproducing plants have the potential to bear a significantly greater mutational load than sexually reproducing species. To investigate this possibility, we examined the breadth of genome-wide structural variation in a panel of monoploid/doubled monoploid clones generated from native populations of diploid potato (Solanum tuberosum), a highly heterozygous asexually propagated plant. As rare instances of purely homozygous clones, they provided an ideal set for determining the degree of structural variation tolerated by this species and deriving its minimal gene complement. Extensive copy number variation (CNV) was uncovered, impacting 219.8 Mb (30.2%) of the potato genome with nearly 30% of genes subject to at least partial duplication or deletion, revealing the highly heterogeneous nature of the potato genome. Dispensable genes (>7000) were associated with limited transcription and/or a recent evolutionary history, with lower deletion frequency observed in genes conserved across angiosperms. Association of CNV with plant adaptation was highlighted by enrichment in gene clusters encoding functions for environmental stress response, with gene duplication playing a part in species-specific expansions of stress-related gene families. This study revealed unique impacts of CNV in a species with asexual reproductive habits and how CNV may drive adaption through evolution of key stress pathways.

A Genome Wide Study of Copy Number Variation Associated with Nasopharyngeal Carcinoma in Malaysian Chinese Identifies CNVs at 11q14.3 and 6p21.3 as Candidate Loci

BackgroundNasopharyngeal carcinoma (NPC) is a neoplasm of the epithelial lining of the nasopharynx. Despite various reports linking genomic variants to NPC predisposition, very few reports were done on copy number variations (CNV). CNV is an inherent structural variation that has been found to be involved in cancer predisposition.MethodsA discovery cohort of Malaysian Chinese descent (NPC patients, n = 140; Healthy controls, n = 256) were genotyped using Illumina® HumanOmniExpress BeadChip. PennCNV and cnvPartition calling algorithms were applied for CNV calling. Taqman CNV assays and digital PCR were used to validate CNV calls and replicate candidate copy number variant region (CNVR) associations in a follow-up Malaysian Chinese (NPC cases, n = 465; and Healthy controls, n = 677) and Malay cohort (NPC cases, n = 114; Healthy controls, n = 124).ResultsSix putative CNVRs overlapping GRM5, MICA/HCP5/HCG26, LILRB3/LILRA6, DPY19L2, RNase3/RNase2 and GOLPH3 genes were jointly identified by PennCNV and cnvPartition. CNVs overlapping GRM5 and MICA/HCP5/HCG26 were subjected to further validation by Taqman CNV assays and digital PCR. Combined analysis in Malaysian Chinese cohort revealed a strong association at CNVR on chromosome 11q14.3 (Pcombined = 1.54x10-5; odds ratio (OR) = 7.27; 95% CI = 2.96–17.88) overlapping GRM5 and a suggestive association at CNVR on chromosome 6p21.3 (Pcombined = 1.29x10-3; OR = 4.21; 95% CI = 1.75–10.11) overlapping MICA/HCP5/HCG26 genes.ConclusionOur results demonstrated the association of CNVs towards NPC susceptibility, implicating a possible role of CNVs in NPC development.

Characterization of copy number variants for CCL3L1 gene in rheumatoid arthritis for French trio families and Tunisian cases and controls.

Analyses of copy number variants (CNVs) for candidate genes in complex diseases are currently a promising research field. CNVs of C-C chemokine ligand 3-like 1 (CCL3L1) gene are candidate genomic factors in rheumatoid arthritis (RA). We investigated CCL3L1 CNVs association with a case-control study in Tunisians and a transmission analysis in French trio families. Relative copy number (rCN) of CCL3L1 gene was quantified by droplet digital PCR (ddPCR) in 100 French trio families (RA patients and their two parents) and in 166 RA cases and 102 healthy controls from Tunisia. We calculated odds ratio (OR) to investigate association risk for CCL3L1 CNVs in RA. rCN identified varied from 0 to 4 in the French population and from 0 to 7 in the Tunisian population. A significant difference was observed in the distribution of these rCNs between the two populations (p = 2.34 × 10(-10)), as when rCN from French and Tunisian RA patients were compared (p = 2.83 × 10(-5)). CNVs transmission in French RA trios allowed the characterization of genotypes with the presence of tandem duplication and triplication on the same chromosome. RA association tests highlighted a protective effect of rCN = 5 for CCL3L1 gene in the Tunisian population (OR = 0.056; CI 95 % [0.01-0.46]). Characterization of CCL3L1 CNVs with ddPCR methodology highlighted specific CN genotypes in a French family sample. A copy number polymorphism of a RA candidate gene was quantified, and its significant association with RA was revealed in a Tunisian sample.

Association of chromosome 17q copy number variation with overall survival of patients with hepatocellular carcinoma and screening of potential target genes

OBJECTIVE To assess the association of copy number variations (CNVs) in chromosome 17q with the overall survival(OS) of patients with hepatocellular carcinoma(HCC), and to screen for target genes contained in the OS-related CNVs. METHODS A total of 174 HCC cases were enrolled. For 66 patients, the follow-up data was available. High-resolution Agilent Hu-244A array comparative genomic hybridization (aCGH) and Affymetrix U133 Plus 2.0 expression arrays were used to detect CNVs and gene expression of genes from the 17q region, respectively. The association of CNVs and OS was assessed with Log-rank test, Kaplan-Meier survival analysis, and Cox proportional hazards models. The gene expression in HCCs with 17q gain, HCCs without, and non-tumor liver tissues were compared with a Mann-Whitney U test. RESULTS Univariate association analysis showed that copy number gain in 17q25.1-25.3 was significantly associated with reduced OS (Log-rank test, P = 0.00002), and HCC cases with 17q25.1-25.3 gain had a 4.76-fold (95%CI: 2.31-9.81) increased hazard ratio (HR) for death from HCC, as compared to those without the gain. Multivariate Cox proportional hazards regression model revealed 17q25.1-25.3 gain to be an independent prognostic marker for poor OS (HR = 3.17, 95%CI: 1.39-7.26, P = 0.006). The expression levels of 18 genes in 17q25.1-25.3 including SLC9A3R1, GRB2, and TK1 were significantly increased in HCCs with gain than in those without (all P < 0.01) and non-tumor liver tissues (all P < 0.01). CONCLUSION The association of 17q25.1-25.3 gain with reduced OS has indicated that it is a prognostic marker for poor patient survival in HCC, for which SLC9A3R1, GRB2, and TK1 are candidate genes.

Copy number variations in multiple sclerosis and neuromyelitis optica.

To clarify the potential association of copy number variations (CNVs) with multiple sclerosis (MS) and neuromyelitis optica (NMO) in Japanese cases. Genome-wide association analyses of CNVs among 277 MS patients, 135 NMO/NMO spectrum disorder (NMOSD) patients, and 288 healthy individuals as a discovery cohort, and among 296 MS patients, 76 NMO/NMOSD patients, and 790 healthy individuals as a replication cohort were performed using high-density single nucleotide polymorphism microarrays. A series of discovery and replication studies revealed that most identified CNVs were 5 to 50kb deletions at particular T cell receptor (TCR) gamma and alpha loci regions. Among these CNVs, a TCR gamma locus deletion was found in 16.40% of MS patients (p = 2.44E-40, odds ratio [OR] = 52.6), and deletion at the TCR alpha locus was found in 17.28% of MS patients (p = 1.70E-31, OR = 13.0) and 13.27% of NMO/NMOSD patients (p = 5.79E-20, OR = 54.6). These CNVs were observed in peripheral blood T-cell subsets only, suggesting the CNVs were somatically acquired. NMO/NMOSD patients carrying the CNV tended to be seronegative for anti-aquaporin-4 antibody or had significantly lower titers than those without CNV. Deletion-type CNVs at specific TCR loci regions contribute to MS and NMO susceptibility.

Copy Number Variations and Cognitive Phenotypes in Unselected Populations

Importance The association of copy number variations (CNVs), differing numbers of copies of genetic sequence at locations in the genome, with phenotypes such as intellectual disability has been almost exclusively evaluated using clinically ascertained cohorts. The contribution of these genetic variants to cognitive phenotypes in the general population remains unclear. Objective To investigate the clinical features conferred by CNVs associated with known syndromes in adult carriers without clinical preselection and to assess the genome-wide consequences of rare CNVs (frequency ≤0.05%; size ≥250 kilobase pairs [kb]) on carriers’ educational attainment and intellectual disability prevalence in the general population. Design, Setting, and Participants The population biobank of Estonia contains 52 000 participants enrolled from 2002 through 2010. General practitioners examined participants and filled out a questionnaire of health- and lifestyle-related questions, as well as reported diagnoses. Copy number variant analysis was conducted on a random sample of 7877 individuals and genotype-phenotype associations with education and disease traits were evaluated. Our results were replicated on a high-functioning group of 993 Estonians and 3 geographically distinct populations in the United Kingdom, the United States, and Italy. Main Outcomes and Measures Phenotypes of genomic disorders in the general population, prevalence of autosomal CNVs, and association of these variants with educational attainment (from less than primary school through scientific degree) and prevalence of intellectual disability. Results Of the 7877 in the Estonian cohort, we identified 56 carriers of CNVs associated with known syndromes. Their phenotypes, including cognitive and psychiatric problems, epilepsy, neuropathies, obesity, and congenital malformations are similar to those described for carriers of identical rearrangements ascertained in clinical cohorts. A genome-wide evaluation of rare autosomal CNVs (frequency, ≤0.05%; ≥250 kb) identified 831 carriers (10.5%) of the screened general population. Eleven of 216 (5.1%) carriers of a deletion of at least 250 kb (odds ratio [OR], 3.16; 95% CI, 1.51-5.98; P = 1.5e-03) and 6 of 102 (5.9%) carriers of a duplication of at least 1 Mb (OR, 3.67; 95% CI, 1.29-8.54; P = .008) had an intellectual disability compared with 114 of 6819 (1.7%) in the Estonian cohort. The mean education attainment was 3.81 ( P = 1.06e-04) among 248 (≥250 kb) deletion carriers and 3.69 (P = 5.024e-05) among 115 duplication carriers (≥1 Mb). Of the deletion carriers, 33.5% did not graduate from high school (OR, 1.48; 95% CI, 1.12-1.95; P = .005) and 39.1% of duplication carriers did not graduate high school (OR, 1.89; 95% CI, 1.27-2.8; P = 1.6e-03). Evidence for an association between rare CNVs and lower educational attainment was supported by analyses of cohorts of adults from Italy and the United States and adolescents from the United Kingdom. Conclusions and Relevance Known pathogenic CNVs in unselected, but assumed to be healthy, adult populations may be associated with unrecognized clinical sequelae. Additionally, individually rare but collectively common intermediate-size CNVs may be negatively associated with educational attainment. Replication of these findings in additional population groups is warranted given the potential implications of this observation for genomics research, clinical care, and public health.

CNV Analysis Associates AKNAD1 with Type-2 Diabetes in Jordan Subpopulations.

Previous studies have identified a number of single nucleotide polymorphisms (SNPs) associated with type-2 diabetes (T2D), but copy number variation (CNV) association has rarely been addressed, especially in populations from Jordan. To investigate CNV associations for T2D in populations in Jordan, we conducted a CNV analysis based on intensity data from genome-wide SNP array, including 34 T2D cases and 110 healthy controls of Chechen ethnicity, as well as 34 T2D cases and 106 healthy controls of Circassian ethnicity. We found a CNV region in protein tyrosine phosphatase receptor type D (PTPRD) with significant association with T2D. PTPRD has been reported to be associated with T2D in genome-wide association studies (GWAS). We additionally identified 16 CNV regions associated with T2D which overlapped with gene exons. Of particular interest, a CNV region in the gene AKNA Domain Containing 1 (AKNAD1) surpassed the experiment-wide significance threshold. Endoplasmic reticulum (ER)-related pathways were significantly enriched among genes which are predicted to be functionally associated with human or mouse homologues of AKNAD1. This is the first CNV analysis of a complex disease in populations of Jordan. We identified and experimentally validated a significant CNVR in gene AKNAD1 associated with T2D.

Association of β-defensin gene copy number variations with ankylosing spondylitis in Chinese population: A case–control study

Objectives. To explore the association of β-defensin gene copy number variations (CNVs) with ankylosing spondylitis (AS).Methods. In this study, 405 unrelated Chinese Han patients with AS and 401 unrelated healthy controls were enrolled. The copy numbers of DEFB4 gene (2 fragments) were measured by AccuCopy™ methods. The association of DEFB4 gene CNVs with AS susceptibility was analyzed by chi-square and logistic regression models. Besides, P values, odds ratio, and 95% confidence intervals (CIs) were used to estimate the effects of risk.Results. The range of DEFB4_1 CN was 0–7 and the range of DEFB4_2 CN was 1–8 both in patients and controls. P values of χ2 trend test for the association of DEFB4_1 and DEFB4_2 with AS were 0.607 and 0.005, respectively. The results of DEFB4_2, compared with the individual having median 3 copies, those carrying ≤ 2-copies [OR = 0.68, 95%CI: (0.46, 0.99), P = 0.049; adjusted OR = 0.69, 95%CI(0.47, 1.03), P = 0.067.]; and those carrying ≥ 4-copies [OR = 0.62, 95%CI: (0.45, 0.86), P = 0.004; adjusted OR = 0.64, 95%CI: (0.46, 0.88), P = 0.006], were significantly associated with decreasing risk of AS. Univariate analysis showed that both DEFB4_1 and DEFB4_2 were associated with Bath AS Disease Activity Index or BASDAI. After adjusted by age, sex, and disease duration, the results changed little, which demonstrated that high copies may be linked with decrease in the risk of disease severity [OR = 0.71, 95%CI: (0.56, 0.90), P = 0.005; OR = 0.75, 95%CI: (0.60, 0.94), P = 0.013, respectively].Conclusions. The CNs of DEFB4 gene may be associated with AS and involved in disease progression.

The association of copy number variation and percent mammographic density.

BackgroundPercent mammographic density (PD) estimates the proportion of stromal, fat, and epithelial breast tissues on the mammogram image. Adjusted for age and body mass index (BMI), PD is one of the strongest risk factors for breast cancer [1]. Inherited factors are hypothesized to explain between 30 and 60% of the variance in this trait [2–5]. However, previously identified common genetic variants account for less than 6% of the variance in PD, leaving much of the genetic contribution to this trait unexplained. We performed the first study to examine whether germline copy number variation (CNV) are associated with PD. Two genome-wide association studies (GWAS) of percent density conducted on the Illumina 660W-Quad were used to identify and replicate the association between candidate CNVs and PD: the Minnesota Breast Cancer Family Study (MBCFS) and controls from the Mayo Venous Thromboembolism (Mayo VTE) Case–Control Study, with 585 and 328 women, respectively. Linear models were utilized to examine the association of each probe with PD, adjusted for age, menopausal status and BMI. Segmentation was subsequently performed on the probe-level test statistics to identify candidate CNV regions that were associated with PD.ResultsSixty-one probes from five chromosomal regions [3q26.1 (2 regions), 8q24.22, 11p15.3, and 17q22] were significantly associated with PD in MBCFS (p-values <0.0001). A CNV at 3q26.1 showed the greatest evidence for association with PD; a region without any known SNPs. Conversely, the CNV at 17q22 was largely due to the association between SNPs and PD in the region. SNPs in the 8q24.22 region have been shown to be associated with risk of many cancers; however, SNPs in this region were not responsible for the observed CNV association. While we were unable to replicate the associations with PD, two of the five CNVs (3q26.1 and 11p15.3) were also observed in the Mayo VTE controls.ConclusionsCNVs may help to explain some of the variability in PD that is currently unexplained by SNPs. While we were able to replicate the existence of two CNVs across the two GWAS studies, we were unable to replicate the associations with PD. Even so, the proximity of the identified CNV regions to loci known to be associated with breast cancer risk suggests further investigation and potentially shared genetic mechanisms underlying the PD and breast cancer association.Electronic supplementary materialThe online version of this article (doi:10.1186/s13104-015-1212-y) contains supplementary material, which is available to authorized users.

Copy number variations and cognitive phenotypes in unselected populations.

The association of copy number variations (CNVs), differing numbers of copies of genetic sequence at locations in the genome, with phenotypes such as intellectual disability has been almost exclusively evaluated using clinically ascertained cohorts. The contribution of these genetic variants to cognitive phenotypes in the general population remains unclear. To investigate the clinical features conferred by CNVs associated with known syndromes in adult carriers without clinical preselection and to assess the genome-wide consequences of rare CNVs (frequency ≤0.05%; size ≥250 kilobase pairs [kb]) on carriers' educational attainment and intellectual disability prevalence in the general population. The population biobank of Estonia contains 52,000 participants enrolled from 2002 through 2010. General practitioners examined participants and filled out a questionnaire of health- and lifestyle-related questions, as well as reported diagnoses. Copy number variant analysis was conducted on a random sample of 7877 individuals and genotype-phenotype associations with education and disease traits were evaluated. Our results were replicated on a high-functioning group of 993 Estonians and 3 geographically distinct populations in the United Kingdom, the United States, and Italy. Phenotypes of genomic disorders in the general population, prevalence of autosomal CNVs, and association of these variants with educational attainment (from less than primary school through scientific degree) and prevalence of intellectual disability. Of the 7877 in the Estonian cohort, we identified 56 carriers of CNVs associated with known syndromes. Their phenotypes, including cognitive and psychiatric problems, epilepsy, neuropathies, obesity, and congenital malformations are similar to those described for carriers of identical rearrangements ascertained in clinical cohorts. A genome-wide evaluation of rare autosomal CNVs (frequency, ≤0.05%; ≥250 kb) identified 831 carriers (10.5%) of the screened general population. Eleven of 216 (5.1%) carriers of a deletion of at least 250 kb (odds ratio [OR], 3.16; 95% CI, 1.51-5.98; P = 1.5e-03) and 6 of 102 (5.9%) carriers of a duplication of at least 1 Mb (OR, 3.67; 95% CI, 1.29-8.54; P = .008) had an intellectual disability compared with 114 of 6819 (1.7%) in the Estonian cohort. The mean education attainment was 3.81 (P = 1.06e-04) among 248 (≥250 kb) deletion carriers and 3.69 (P = 5.024e-05) among 115 duplication carriers (≥1 Mb). Of the deletion carriers, 33.5% did not graduate from high school (OR, 1.48; 95% CI, 1.12-1.95; P = .005) and 39.1% of duplication carriers did not graduate high school (OR, 1.89; 95% CI, 1.27-2.8; P = 1.6e-03). Evidence for an association between rare CNVs and lower educational attainment was supported by analyses of cohorts of adults from Italy and the United States and adolescents from the United Kingdom. Known pathogenic CNVs in unselected, but assumed to be healthy, adult populations may be associated with unrecognized clinical sequelae. Additionally, individually rare but collectively common intermediate-size CNVs may be negatively associated with educational attainment. Replication of these findings in additional population groups is warranted given the potential implications of this observation for genomics research, clinical care, and public health.