Autosome-wide Copy Number Variation Association Analysis for Rheumatoid Arthritis Using the WTCCC High-density SNP Genotype Data

2011 ◽  
Vol 38 (5) ◽  
pp. 797-801 ◽  
Author(s):  
MOHAMMED UDDIN ◽  
MITCH STURGE ◽  
PROTON RAHMAN ◽  
MICHAEL O. WOODS
Keyword(s):  
Rheumatoid Arthritis ◽  
Association Analysis ◽  
Lupus Erythematosus ◽  
Copy Number ◽  
Association Studies ◽  
Copy Number Variations ◽  
Transcription Activator ◽  
Variable Regions ◽  
Genome Wide ◽  
A Genome

Objective.Rheumatoid arthritis (RA) is a complex autoimmune rheumatic disease that is strongly influenced by genetic factors. Numerous genes are convincingly associated with RA, including genes in tumor necrosis factor signaling (TNF) and the nuclear factor-κB pathway. To date, except for genes within the HLA region, no data exist regarding potential copy number variations (CNV) involving RA-associated genes. We set out to identify genes affected by CNV that are associated with RA at a genome-wide level.Methods.Data from the Wellcome Trust Case Control Consortium (WTCCC) were used in our analyses. The initial WTCCC cohort genotyped 3004 controls and 1999 RA cases using the GeneChip 500k Mapping Array Set. We performed a comparative intensity analysis using the PennCNV algorithm, which uses a hidden Markov model to detect CNV. A total of 2271 controls and 1572 RA samples passed quality control criteria and were included for association analysis. Association analysis was performed in 2 phases: (1) to identify CNV that are < 1 Mb with a population frequency < 5%; and (2) to identify large CNV that are > 1 Mb. Fishers’ exact test was performed to quantify significance of the CNV.Results.We observed that the genome-wide CNV burden is 2-fold higher in patients with RA compared with controls. We identified 11 rare copy number variable regions with < 5% frequency that had an association with RA that reached a p < 1 × 10−4. These include TNFAIP3 and TNIP1, which has been implicated in association studies for RA, systemic lupus erythematosus, and psoriasis. We identified CNV involving IRF1, which functions as a transcription activator of genes induced by interferons; ALOX5AP and LCP2, involved in inflammatory mediation; B2M, an MHC-class I associated gene; and PRKCH, a gene involved in T cell signaling pathways. A 57 kb deletion with 1% frequency in RA cases at 7p21.3 was also observed. Six of these loci overlap with CNV catalogued in the Database of Genomic Variants.Conclusion.This is the first study to identify non-HLA RA-associated CNV using genome-wide analyses. Validation and functional significance of these deletions/duplications in RA and other autoimmune diseases need to be further investigated.

scholarly journals X-CNV: genome-wide prediction of the pathogenicity of copy number variations

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Li Zhang ◽  
Jingru Shi ◽  
Jian Ouyang ◽  
Riquan Zhang ◽  
Yiran Tao ◽  
...  
Keyword(s):  
Ethnic Groups ◽  
Copy Number ◽  
Association Studies ◽  
Gene Copy Number ◽  
Copy Number Variations ◽  
Gene Copy ◽  
Computational Framework ◽  
Genome Wide ◽  
Pathogenicity Prediction ◽  
A Genome

Abstract Background Gene copy number variations (CNVs) contribute to genetic diversity and disease prevalence across populations. Substantial efforts have been made to decipher the relationship between CNVs and pathogenesis but with limited success. Results We have developed a novel computational framework X-CNV (www.unimd.org/XCNV), to predict the pathogenicity of CNVs by integrating more than 30 informative features such as allele frequency (AF), CNV length, CNV type, and some deleterious scores. Notably, over 14 million CNVs across various ethnic groups, covering nearly 93% of the human genome, were unified to calculate the AF. X-CNV, which yielded area under curve (AUC) values of 0.96 and 0.94 in training and validation sets, was demonstrated to outperform other available tools in terms of CNV pathogenicity prediction. A meta-voting prediction (MVP) score was developed to quantitively measure the pathogenic effect, which is based on the probabilistic value generated from the XGBoost algorithm. The proposed MVP score demonstrated a high discriminative power in determining pathogenetic CNVs for inherited traits/diseases in different ethnic groups. Conclusions The ability of the X-CNV framework to quantitatively prioritize functional, deleterious, and disease-causing CNV on a genome-wide basis outperformed current CNV-annotation tools and will have broad utility in population genetics, disease-association studies, and diagnostic screening.

scholarly journals Retrospective Association Analysis of Longitudinal Binary Traits Identifies Important Loci and Pathways in Cocaine Use

Genetics ◽  
2019 ◽  
Vol 213 (4) ◽  
pp. 1225-1236 ◽  
Author(s):  
Weimiao Wu ◽  
Zhong Wang ◽  
Ke Xu ◽  
Xinyu Zhang ◽  
Amei Amei ◽  
...  
Keyword(s):  
Association Analysis ◽  
Binary Data ◽  
Association Studies ◽  
Association Test ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Cocaine Use ◽  
Genome Wide ◽  
A Genome ◽  
Time Varying Covariates

Longitudinal phenotypes have been increasingly available in genome-wide association studies (GWAS) and electronic health record-based studies for identification of genetic variants that influence complex traits over time. For longitudinal binary data, there remain significant challenges in gene mapping, including misspecification of the model for phenotype distribution due to ascertainment. Here, we propose L-BRAT (Longitudinal Binary-trait Retrospective Association Test), a retrospective, generalized estimating equation-based method for genetic association analysis of longitudinal binary outcomes. We also develop RGMMAT, a retrospective, generalized linear mixed model-based association test. Both tests are retrospective score approaches in which genotypes are treated as random conditional on phenotype and covariates. They allow both static and time-varying covariates to be included in the analysis. Through simulations, we illustrated that retrospective association tests are robust to ascertainment and other types of phenotype model misspecification, and gain power over previous association methods. We applied L-BRAT and RGMMAT to a genome-wide association analysis of repeated measures of cocaine use in a longitudinal cohort. Pathway analysis implicated association with opioid signaling and axonal guidance signaling pathways. Lastly, we replicated important pathways in an independent cocaine dependence case-control GWAS. Our results illustrate that L-BRAT is able to detect important loci and pathways in a genome scan and to provide insights into genetic architecture of cocaine use.

scholarly journals Genome-Wide Copy Number Variation Association Study of Atrial Fibrillation Related Thromboembolic Stroke

2019 ◽  
Vol 8 (3) ◽  
pp. 332 ◽  
Author(s):  
Chia-Shan Hsieh ◽  
Pang-Shuo Huang ◽  
Sheng-Nan Chang ◽  
Cho-Kai Wu ◽  
Juey-Jen Hwang ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Signaling Pathway ◽  
Copy Number ◽  
Genetic Factors ◽  
Copy Number Variations ◽  
Nucleotide Polymorphisms ◽  
Thromboembolic Stroke ◽  
Genome Wide ◽  
A Genome ◽  
The Impact

Atrial fibrillation (AF) is a common cardiac arrhythmia and is one of the major causes of ischemic stroke. In addition to the clinical factors such as CHADS2 or CHADS2-VASC score, the impact of genetic factors on the risk of thromboembolic stroke in patients with AF has been largely unknown. Single-nucleotide polymorphisms in several genomic regions have been found to be associated with AF. However, these loci do not contribute to all the genetic risks of AF or AF related thromboembolic risks, suggesting that there are other genetic factors or variants not yet discovered. In the human genome, copy number variations (CNVs) could also contribute to disease susceptibility. In the present study, we sought to identify CNVs determining the AF-related thromboembolic risk. Using a genome-wide approach in 109 patients with AF and thromboembolic stroke and 14,666 controls from the Taiwanese general population (Taiwan Biobank), we first identified deletions in chromosomal regions 1p36.32-1p36.33, 5p15.33, 8q24.3 and 19p13.3 and amplifications in 14q11.2 that were significantly associated with AF-related stroke in the Taiwanese population. In these regions, 148 genes were involved, including several microRNAs and long non-recoding RNAs. Using a pathway analysis, we found deletions in GNB1, PRKCZ, and GNG7 genes related to the alpha-adrenergic receptor signaling pathway that play a major role in determining the risk of an AF-related stroke. In conclusion, CNVs may be genetic predictors of a risk of a thromboembolic stroke for patients with AF, possibly pointing to an impaired alpha-adrenergic signaling pathway in the mechanism of AF-related thromboembolism.

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

2016 ◽  
Vol 47 (3) ◽  
pp. 298-305 ◽  
Author(s):  
Yi Long ◽  
Ying Su ◽  
Huashui Ai ◽  
Zhiyan Zhang ◽  
Bin Yang ◽  
...  
Keyword(s):  
Association Study ◽  
Copy Number ◽  
Umbilical Hernia ◽  
Genome Wide Association Study ◽  
Copy Number Variations ◽  
Genome Wide Association ◽  
Genome Wide ◽  
A Genome

scholarly journals Genome-wide association analysis of copy number variations in subarachnoid aneurysmal hemorrhage

2010 ◽  
Vol 55 (11) ◽  
pp. 726-730 ◽  
Author(s):  
Joon Seol Bae ◽  
Hyun Sub Cheong ◽  
Byung Lae Park ◽  
Lyoung Hyo Kim ◽  
Tae Joon Park ◽  
...  
Keyword(s):  
Association Analysis ◽  
Copy Number ◽  
Copy Number Variations ◽  
Genome Wide Association ◽  
Genome Wide Association Analysis ◽  
Genome Wide

scholarly journals Comparative analyses of copy number variations between Bos taurus and Bos indicus

BMC Genomics ◽  
2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Yan Hu ◽  
Han Xia ◽  
Mingxun Li ◽  
Chang Xu ◽  
Xiaowei Ye ◽  
...  
Keyword(s):  
Copy Number ◽  
Muscle Development ◽  
Reference Genome ◽  
Bos Taurus ◽  
Bos Indicus ◽  
Copy Number Variations ◽  
Genome Wide ◽  
A Genome ◽  
Detection Strategies ◽  
Specific Sequences

Abstract Background Bos taurus and Bos indicus are two main sub-species of cattle. However, the differential copy number variations (CNVs) between them are not yet well studied. Results Based on the new high-quality cattle reference genome ARS-UCD1.2, we identified 13,234 non-redundant CNV regions (CNVRs) from 73 animals of 10 cattle breeds (4 Bos taurus and 6 Bos indicus), by integrating three detection strategies. While 6990 CNVRs (52.82%) were shared by Bos taurus and Bos indicus, large CNV differences were discovered between them and these differences could be used to successfully separate animals into two subspecies. We found that 2212 and 538 genes uniquely overlapped with either indicine-specific CNVRs and or taurine-specific CNVRs, respectively. Based on FST, we detected 16 candidate lineage-differential CNV segments (top 0.1%) under selection, which overlapped with eight genes (CTNNA1, ENSBTAG00000004415, PKN2, BMPER, PDE1C, DNAJC18, MUSK, and PLCXD3). Moreover, we obtained 1.74 Mbp indicine-specific sequences, which could only be mapped on the Bos indicus reference genome UOA_Brahman_1. We found these sequences and their associated genes were related to heat resistance, lipid and ATP metabolic process, and muscle development under selection. We further analyzed and validated the top significant lineage-differential CNV. This CNV overlapped genes related to muscle cell differentiation, which might be generated from a retropseudogene of CTH but was deleted along Bos indicus lineage. Conclusions This study presents a genome wide CNV comparison between Bos taurus and Bos indicus. It supplied essential genome diversity information for understanding of adaptation and phenotype differences between the Bos taurus and Bos indicus populations.

scholarly journals Genome-wide copy number variations in a large cohort of bantu African children

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Feyza Yilmaz ◽  
Megan Null ◽  
David Astling ◽  
Hung-Chun Yu ◽  
Joanne Cole ◽  
...  
Keyword(s):  
Copy Number ◽  
Developmental Disorders ◽  
African Ancestry ◽  
22Q11.2 Deletion Syndrome ◽  
Copy Number Variations ◽  
Genomic Variation ◽  
Deletion Syndrome ◽  
Genome Wide ◽  
A Genome ◽  
Genomic Regions

Abstract Background Copy number variations (CNVs) account for a substantial proportion of inter-individual genomic variation. However, a majority of genomic variation studies have focused on single-nucleotide variations (SNVs), with limited genome-wide analysis of CNVs in large cohorts, especially in populations that are under-represented in genetic studies including people of African descent. Methods We carried out a genome-wide copy number analysis in > 3400 healthy Bantu Africans from Tanzania. Signal intensity data from high density (> 2.5 million probes) genotyping arrays were used for CNV calling with three algorithms including PennCNV, DNAcopy and VanillaICE. Stringent quality metrics and filtering criteria were applied to obtain high confidence CNVs. Results We identified over 400,000 CNVs larger than 1 kilobase (kb), for an average of 120 CNVs (SE = 2.57) per individual. We detected 866 large CNVs (≥ 300 kb), some of which overlapped genomic regions previously associated with multiple congenital anomaly syndromes, including Prader-Willi/Angelman syndrome (Type1) and 22q11.2 deletion syndrome. Furthermore, several of the common CNVs seen in our cohort (≥ 5%) overlap genes previously associated with developmental disorders. Conclusions These findings may help refine the phenotypic outcomes and penetrance of variations affecting genes and genomic regions previously implicated in diseases. Our study provides one of the largest datasets of CNVs from individuals of African ancestry, enabling improved clinical evaluation and disease association of CNVs observed in research and clinical studies in African populations.

scholarly journals Identification of Copy Number Variation Among Nonsyndromic Cleft Lip and or Without Cleft Palate With Hypodontia: A Genome-Wide Association Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Norliana Ghazali ◽  
Normastura Abd Rahman ◽  
Azlina Ahmad ◽  
Sarina Sulong ◽  
Thirumulu Ponnuraj Kannan
Keyword(s):  
Copy Number Variation ◽  
Cleft Palate ◽  
Copy Number ◽  
Cleft Lip ◽  
Genome Wide Association Study ◽  
Quantitative Polymerase Chain Reaction ◽  
Copy Number Variations ◽  
Genome Wide ◽  
A Genome ◽  
Number Variation

Nonsyndromic cleft lip and or without cleft palate (NSCL/P) with the hypodontia is a common developmental abnormality in humans and animals. This study identified the genetic aberration involved in both NSCL/P and hypodontia pathogenesis. A cross-sectional study using genome-wide study copy number variation-targeted CytoScan 750K array carried out on salivary samples from 61 NSCL/P and 20 noncleft with and without hypodontia Malay subjects aged 7–13 years old. Copy number variations (CNVs) of SKI and fragile histidine triad (FHIT) were identified in NSCL/P and noncleft children using quantitative polymerase chain reaction (qPCR) as a validation analysis. Copy number calculated (CNC) for each gene determined with Applied Biosystems CopyCaller Software v2.0. The six significant CNVs included gains (12q14.3, 15q26.3, 1p36.32, and 1p36.33) and losses (3p14.2 and 4q13.2) in NSCL/P with hypodontia patients compared with the NSCL/P only. The genes located in these regions encoded LEMD3, IGF1R, TP73, SKI, FHIT, and UGT2β15. There were a significant gain and loss of both SKI and FHIT copy number in NSCL/P with hypodontia compared with the noncleft group (p &lt; 0.05). The results supported that CNVs significantly furnish to the development of NSCL/P with hypodontia.

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