scholarly journals Rare copy number variants in NRXN1 and CNTN6 increase risk for Tourette syndrome

2016 ◽  
Author(s):  
Alden Y. Huang ◽  
Dongmei Yu ◽  
Lea K. Davis ◽  
Jae-Hoon Sul ◽  
Fotis Tsetsos ◽  
...  
Keyword(s):  
Tourette Syndrome ◽  
Copy Number ◽  
Genetic Architecture ◽  
Structural Variation ◽  
Copy Number Variants ◽  
European Ancestry ◽  
Genome Wide ◽  
Snp Microarrays ◽  
Increase Risk ◽  
Increase In Risk

Tourette syndrome (TS) is highly heritable, although identification of its underlying genetic cause(s) has remained elusive. We examined a European ancestry sample composed of 2,435 TS cases and 4,100 controls for copy-number variants (CNVs) using SNP microarrays and identified two genome-wide significant loci that confer a substantial increase in risk for TS (NRXN1, OR=20.3, 95%CI [2.6-156.2], p=6.0 × 10−6; CNTN6, OR=10.1, 95% CI [2.3-45.4], p=3.7 × 10−5). Approximately 1% of TS cases carried one of these CNVs, indicating that rare structural variation contributes significantly to the genetic architecture of TS.

scholarly journals Evaluation of copy number burden in specific epilepsy types from a genome-wide study of 18,564 subjects

2019 ◽  
Author(s):  
Lisa-Marie Niestroj ◽  
Daniel P. Howrigan ◽  
Eduardo Perez-Palma ◽  
Elmo Saarentaus ◽  
Peter Nürnberg ◽  
...  
Keyword(s):  
Copy Number ◽  
Genetic Architecture ◽  
Focal Epilepsy ◽  
Copy Number Variants ◽  
Epileptic Encephalopathy ◽  
Additional Risk ◽  
Genome Wide ◽  
A Genome ◽  
Generalized Epilepsy ◽  
Genome Wide Study

AbstractRare and large copy number variants (CNVs) around known genomic ‘hotspots’ are strongly implicated in epilepsy etiology. But it remains unclear whether the observed associations are specific to an epilepsy phenotype, and if additional risk signal can be found outside hotspots. Here, we present the largest CNV burden and first CNV breakpoint level association analysis in epilepsy to date with 11,246 European epilepsy cases and 7,318 ancestry-matched controls. We studied five epilepsy phenotypes: genetic generalized epilepsy, lesional focal epilepsy, non-acquired focal epilepsy, epileptic encephalopathy, and unclassified epilepsy. We discovered novel epilepsy-associated CNV loci and further characterized the CNV burden enrichment among phenotype-specific epilepsies. Finally, we provide evidence for deletion burden outside of known hotspot regions and show that CNVs play a significant role in the genetic architecture of lesional focal epilepsies.

scholarly journals Rare Copy Number Variants in NRXN1 and CNTN6 Increase Risk for Tourette Syndrome

Neuron ◽  
2017 ◽  
Vol 94 (6) ◽  
pp. 1101-1111.e7 ◽  
Author(s):  
Alden Y. Huang ◽  
Dongmei Yu ◽  
Lea K. Davis ◽  
Jae Hoon Sul ◽  
Fotis Tsetsos ◽  
...  
Keyword(s):  
Tourette Syndrome ◽  
Copy Number ◽  
Copy Number Variants ◽  
Increase Risk

scholarly journals Rare copy number variants (CNVs) and breast cancer risk

2021 ◽  
Author(s):  
Joe Dennis ◽  
Jonathan P. Tyrer ◽  
Logan C. Walker ◽  
Kyriaki Michailidou ◽  
Leila Dorling ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Copy Number ◽  
Statistical Significance ◽  
Copy Number Variants ◽  
Susceptibility Genes ◽  
European Ancestry ◽  
Rare Cnvs ◽  
Cancer Susceptibility Genes ◽  
Large Breast ◽  
Genome Wide

Background: Copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Results: Gene burden tests detected the strongest association for deletions in BRCA1 (P= 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P= 0.0008), ATM (P= 0.002) and BRCA2 (P= 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci. Conclusions: This is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.

scholarly journals Rare Copy Number Variants (CNVs) and Breast Cancer Risk

2021 ◽  
Author(s):  
Joe Dennis ◽  
Jonathan Tyrer ◽  
Logan Walker ◽  
Kyriaki Michailidou ◽  
Leila Dorling ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Copy Number ◽  
Statistical Significance ◽  
Copy Number Variants ◽  
Susceptibility Genes ◽  
European Ancestry ◽  
Rare Cnvs ◽  
Cancer Susceptibility Genes ◽  
Large Breast ◽  
Genome Wide

Abstract BackgroundCopy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data.ResultsGene burden tests detected the strongest association for deletions in BRCA1 (P= 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P= 0.0008), ATM (P= 0.002) and BRCA2 (P= 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci.ConclusionsThis is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.

scholarly journals Detection and characterization of copy number variants based on whole-genome sequencing by DNBSEQ platforms

2019 ◽  
Author(s):  
Junhua Rao ◽  
Lihua Peng ◽  
Fang Chen ◽  
Hui Jiang ◽  
Chunyu Geng ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Copy Number ◽  
Copy Number Variants ◽  
Copy Number Variant ◽  
Whole Genome ◽  
Genome Wide ◽  
Wide Range ◽  
Distribution Sensitivity ◽  
Cnv Detection

AbstractBackgroundNext-generation sequence (NGS) has rapidly developed in past years which makes whole-genome sequencing (WGS) becoming a more cost- and time-efficient choice in wide range of biological researches. We usually focus on some variant detection via WGS data, such as detection of single nucleotide polymorphism (SNP), insertion and deletion (Indel) and copy number variant (CNV), which playing an important role in many human diseases. However, the feasibility of CNV detection based on WGS by DNBSEQ™ platforms was unclear. We systematically analysed the genome-wide CNV detection power of DNBSEQ™ platforms and Illumina platforms on NA12878 with five commonly used tools, respectively.ResultsDNBSEQ™ platforms showed stable ability to detect slighter more CNVs on genome-wide (average 1.24-fold than Illumina platforms). Then, CNVs based on DNBSEQ™ platforms and Illumina platforms were evaluated with two public benchmarks of NA12878, respectively. DNBSEQ™ and Illumina platforms showed similar sensitivities and precisions on both two benchmarks. Further, the difference between tools for CNV detection was analyzed, and indicated the selection of tool for CNV detection could affected the CNV performance, such as count, distribution, sensitivity and precision.ConclusionThe major contribution of this paper is providing a comprehensive guide for CNV detection based on WGS by DNBSEQ™ platforms for the first time.

scholarly journals Bayesian copy number detection and association in large-scale studies

2020 ◽  
Author(s):  
Stephen Cristiano ◽  
David McKean ◽  
Jacob Carey ◽  
Paige Bracci ◽  
Paul Brennan ◽  
...  
Keyword(s):  
Copy Number ◽  
Large Scale ◽  
Disease Risk ◽  
Copy Number Variants ◽  
Regulatory Elements ◽  
Cancer Case ◽  
Tumor Supressor ◽  
Increase Risk ◽  
Control Study

AbstractGermline copy number variants (CNVs) increase risk for many diseases, yet detection of CNVs and quantifying their contribution to disease risk in large-scale studies is challenging. We developed an approach called CNPBayes to identify latent batch effects, to provide probabilistic estimates of integer copy number across the estimated batches, and to fully integrate the copy number uncertainty in the association model for disease. We demonstrate this approach in a Pancreatic Cancer Case Control study of 7,598 participants where the major sources of technical variation were not captured by study site and varied across the genome. Candidate associations aided by this approach include deletions of 8q24 near regulatory elements of the tumor oncogene MYC and of Tumor Supressor Candidate 3 (TUSC3). This study provides a robust Bayesian inferential framework for estimating copy number and evaluating the role of copy number in heritable diseases.

scholarly journals Unraveling the genetic architecture of copy number variants associated with schizophrenia and other neuropsychiatric disorders

2016 ◽  
Vol 95 (5) ◽  
pp. 1144-1160 ◽  
Author(s):  
Timothy P. Rutkowski ◽  
Jason P. Schroeder ◽  
Georgette M. Gafford ◽  
Stephen T. Warren ◽  
David Weinshenker ◽  
...  
Keyword(s):  
Copy Number ◽  
Genetic Architecture ◽  
Copy Number Variants ◽  
Neuropsychiatric Disorders

Abstract 16160: Common Autosomal Variants are Associated With Bicuspid Aortic Valve in Turner Syndrome

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Siddharth Prakash ◽  
Michael Silberbach ◽  
Federico Asch ◽  
Giuseppe Limongelli ◽  
Hector Michelena ◽  
...  
Keyword(s):  
Turner Syndrome ◽  
Meta Analysis ◽  
Copy Number Variants ◽  
European Ancestry ◽  
P Value ◽  
Scaling Analysis ◽  
Aortic Valves ◽  
Genome Wide ◽  
Independent Review ◽  
Tests Of Association

Introduction: The prevalence of bicuspid aortic valves (BAV) is enriched thirty-fold in women with Turner Syndrome (TS) in comparison with the general population. Hypothesis: Common autosomal variants influence the development of BAV in TS women, who may be uniquely sensitized to these variants by the loss of one X chromosome. We sought to identify autosomal BAV susceptibility genes in a cohort of TS women (average age 30 years, 38% BAV, 18% coarctation). Methods: A total of 106 TS women of European ancestry with BAV and 173 TS women with tricuspid aortic valves were genotyped on Illumina Omni-Express arrays. Valve phenotypes were determined by independent review of echocardiograms from the enrolling sites. Tests of association were performed using logistic regression without adjustment for covariates and were summarized in a meta-analysis. Results: Xp dosage was inversely and quantitatively associated with BAV status (P=0.02). Large, recurrent copy number variants in 1p36.13, 3q29, 8p23.1 and 9p24.3 were significantly enriched in BAV cases. After exclusion of 26 outlier samples in multidimensional scaling analysis, there was no significant genomic inflation (lambda= 1.02). The strongest genome-wide association signals were observed in 1p36.23, 3q23, 12q21.2, 18q21 and 22q13.31, and did not overlap with previously reported loci for BAV. A total of 13 SNPs in 18q21 were positively associated with BAV (OR=2.5-4.3) with a minimum P value of 1x10-7. Replication of these regions in independent groups of cases is ongoing. Conclusion: Our results demonstrate that autosomal variants with large magnitudes of effect contribute to BAV in TS women, confirming our hypothesis, and provide evidence for gene-gene interactions in BAV formation.

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