scholarly journals Epilepsy subtype-specific copy number burden observed in a genome-wide study of 17 458 subjects

Brain ◽  
2020 ◽  
Vol 143 (7) ◽  
pp. 2106-2118 ◽  
Author(s):  
Lisa-Marie Niestroj ◽  
Eduardo Perez-Palma ◽  
Daniel P Howrigan ◽  
Yadi Zhou ◽  
Feixiong Cheng ◽  
...  
Keyword(s):  
Copy Number ◽  
Focal Epilepsy ◽  
Copy Number Variants ◽  
Epileptic Encephalopathy ◽  
Human Interactome ◽  
Genome Wide ◽  
A Genome ◽  
Wide Scale ◽  
Generalized Epilepsy ◽  
First Time

Abstract Cytogenic testing is routinely applied in most neurological centres for severe paediatric epilepsies. However, which characteristics of copy number variants (CNVs) confer most epilepsy risk and which epilepsy subtypes carry the most CNV burden, have not been explored on a genome-wide scale. Here, we present the largest CNV investigation in epilepsy to date with 10 712 European epilepsy cases and 6746 ancestry-matched controls. Patients with genetic generalized epilepsy, lesional focal epilepsy, non-acquired focal epilepsy, and developmental and epileptic encephalopathy were included. All samples were processed with the same technology and analysis pipeline. All investigated epilepsy types, including lesional focal epilepsy patients, showed an increase in CNV burden in at least one tested category compared to controls. However, we observed striking differences in CNV burden across epilepsy types and investigated CNV categories. Genetic generalized epilepsy patients have the highest CNV burden in all categories tested, followed by developmental and epileptic encephalopathy patients. Both epilepsy types also show association for deletions covering genes intolerant for truncating variants. Genome-wide CNV breakpoint association showed not only significant loci for genetic generalized and developmental and epileptic encephalopathy patients but also for lesional focal epilepsy patients. With a 34-fold risk for developing genetic generalized epilepsy, we show for the first time that the established epilepsy-associated 15q13.3 deletion represents the strongest risk CNV for genetic generalized epilepsy across the whole genome. Using the human interactome, we examined the largest connected component of the genes overlapped by CNVs in the four epilepsy types. We observed that genetic generalized epilepsy and non-acquired focal epilepsy formed disease modules. In summary, we show that in all common epilepsy types, 1.5–3% of patients carry epilepsy-associated CNVs. The characteristics of risk CNVs vary tremendously across and within epilepsy types. Thus, we advocate genome-wide genomic testing to identify all disease-associated types of CNVs.

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 A genome-wide study shows a limited contribution of rare copy number variants to Alzheimer's disease risk

2012 ◽  
Vol 22 (4) ◽  
pp. 816-824 ◽  
Author(s):  
Jade Chapman ◽  
Elliott Rees ◽  
Denise Harold ◽  
Dobril Ivanov ◽  
Amy Gerrish ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Copy Number ◽  
Disease Risk ◽  
Copy Number Variants ◽  
Genome Wide ◽  
A Genome ◽  
Genome Wide Study

A Genome-Wide Screen Of Functional Dna Copy Number Variants Identifies Several Novel Asthma Genes

2011 ◽  
Author(s):  
Angela J. Rogers ◽  
Jen-Hwa Chu ◽  
Katayoon Darvishi ◽  
Iuliana Ionita-Laza ◽  
Barbara J. Klanderman ◽  
...  
Keyword(s):  
Copy Number ◽  
Copy Number Variants ◽  
Dna Copy Number ◽  
Genome Wide ◽  
A Genome ◽  
Functional Dna ◽  
Dna Copy Number Variants

A genome-wide scan of copy number variants using high-density SNPs in Brown Swiss dairy cattle

2016 ◽  
Vol 191 ◽  
pp. 153-160 ◽  
Author(s):  
R.T.M.M. Prinsen ◽  
M.G. Strillacci ◽  
F. Schiavini ◽  
E. Santus ◽  
A. Rossoni ◽  
...  
Keyword(s):  
Dairy Cattle ◽  
Copy Number ◽  
Copy Number Variants ◽  
High Density ◽  
Brown Swiss ◽  
Genome Wide ◽  
A Genome ◽  
Genome Wide Scan

scholarly journals Three years of clinical experience with a genome-wide cfDNA screening test for aneuploidies and copy-number variants

2021 ◽  
Author(s):  
Erica Soster ◽  
Theresa Boomer ◽  
Susan Hicks ◽  
Samantha Caldwell ◽  
Brittany Dyr ◽  
...  
Keyword(s):  
Test Performance ◽  
Copy Number ◽  
Clinical Performance ◽  
Diagnostic Testing ◽  
Copy Number Variants ◽  
High Sensitivity ◽  
Clinical Population ◽  
Genome Wide ◽  
A Genome ◽  
Cfdna Screening

Abstract Purpose Pregnant women have unprecedented choices for prenatal screening and testing. Cell-free DNA (cfDNA) offers the option to screen for aneuploidy of all chromosomes and genome-wide copy-number variants (CNVs), expanding screening beyond the common trisomies (“traditional” cfDNA). We sought to review the utilization trends and clinical performance characteristics of a commercially available genome-wide cfDNA test, with a subset having available diagnostic testing outcomes. Methods Retrospective analysis of 55,517 samples submitted for genome-wide cfDNA screening at a commercial laboratory, assessing indications, demographics, results, and performance. The cohort was broken into three “testing years”’ to compare trends. Results Indications shifted over time, with a decrease in referrals for ultrasound findings (22.0% to 12.0%) and an increase in no known high-risk indication (3.0% to 16.6%). Of the positive results, 25% would be missed with traditional cfDNA screening. High sensitivity and specificity were observed with a positive predictive value (PPV) of 72.6% for genome-wide CNVs and 22.4% for rare autosomal trisomies (RATs). Conclusion A broader patient population is utilizing genome-wide cfDNA, yet positivity rates and the contribution of genome-wide events have remained stable at approximately 5% and 25%, respectively. Test performance in a real-world clinical population shows high PPVs in those CNVs tested, with diagnostic outcomes in over 40% of positive cases.

scholarly journals A genome-wide assessment of rare copy number variants in colorectal cancer

Oncotarget ◽  
2015 ◽  
Vol 6 (28) ◽  
pp. 26411-26423 ◽  
Author(s):  
Zhenli Li ◽  
Dan Yu ◽  
Meifu Gan ◽  
Qiaonan Shan ◽  
Xiaoyang Yin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Copy Number ◽  
Copy Number Variants ◽  
Genome Wide ◽  
A Genome

Genome-wide association study identified copy number variants associated with sporadic colorectal cancer risk

2017 ◽  
Vol 55 (3) ◽  
pp. 181-188 ◽  
Author(s):  
Lai Fun Thean ◽  
Yee Syuen Low ◽  
Michelle Lo ◽  
Yik-Ying Teo ◽  
Woon-Puay Koh ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Association Study ◽  
Copy Number ◽  
Genome Wide Association Study ◽  
Copy Number Variants ◽  
Genome Wide Association ◽  
Copy Number Loss ◽  
Genome Wide ◽  
A Genome

BackgroundMultiple single nucleotide polymorphisms (SNPs) have been associated with colorectal cancer (CRC) risk. The role of structural or copy number variants (CNV) in CRC, however, remained unclear. We investigated the role of CNVs in patients with sporadic CRC.MethodsA genome-wide association study (GWAS) was performed on 1000 Singapore Chinese patients aged 50 years or more with no family history of CRC and 1000 ethnicity-matched, age-matched and gender-matched healthy controls using the Affymetrix SNP 6 platform. After 16 principal component corrections, univariate and multivariate segmentations followed by association testing were performed on 1830 samples that passed quality assurance tests.ResultsA rare CNV region (CNVR) at chromosome 14q11 (OR=1.92 (95% CI 1.59 to 2.32), p=2.7e-12) encompassing CHD8, and common CNVR at chromosomes 3q13.12 (OR=1.54 (95% CI 1.33 to 1.77), p=2.9e-9) and 12p12.3 (OR=1.69 (95% CI 1.41 to 2.01), p=2.8e-9) encompassing CD47 and RERG/ARHGDIB, respectively, were significantly associated with CRC risk. CNV loci were validated in an independent replication panel using an optimised copy number assay. Whole-genome expression data in matched tumours of a subset of cases demonstrated that copy number loss at CHD8 was significantly associated with dysregulation of several genes that perturb the Wnt, TP53 and inflammatory pathways.ConclusionsA rare CNVR at 14q11 encompassing the chromatin modifier CHD8 was significantly associated with sporadic CRC risk. Copy number loss at CHD8 altered expressions of genes implicated in colorectal tumourigenesis.

scholarly journals Regulation of global transcription inE. coliby Rsd and 6S RNA

2016 ◽  
Author(s):  
Avantika Lal ◽  
Sandeep Krishna ◽  
Aswin Sai Narain Seshasayee
Keyword(s):  
Rna Polymerase ◽  
Sigma Factor ◽  
Global Gene Expression ◽  
Rna Seq ◽  
Genome Wide ◽  
A Genome ◽  
6S Rna ◽  
Wide Scale ◽  
Five Phases ◽  
First Time

ABSTRACTInEscherichia coli, the sigma factor σ70directs RNA polymerase to transcribe growth-related genes, while σ38directs transcription of stress response genes during stationary phase. Two molecules hypothesized to regulate RNA polymerase are the protein Rsd, which binds to σ70, and the non-coding 6S RNA which binds to the RNA polymerase- σ70holoenzyme. Despite multiple studies, the functions of Rsd and 6S RNA remain controversial. Here we use RNA-Seq in five phases of growth to elucidate their function on a genome-wide scale. We show for the first time that Rsd and 6S RNA facilitate σ38activity throughout bacterial growth, while 6S RNA also regulates widely different genes depending upon growth phase. We discover novel interactions between 6S RNA and Rsd and show widespread expression changes in a strain lacking both regulators. Finally, we present a mathematical model of transcription which highlights the crosstalk between Rsd and 6S RNA as a crucial factor in controlling sigma factor competition and global gene expression.

scholarly journals Genome-wide Analysis of Copy Number Variation in Latin American Parkinson's Disease Patients

2020 ◽  
Author(s):  
Elif Irem Sarihan ◽  
Eduardo Perez-Palma ◽  
Lisa-Marie Niestroj ◽  
Douglas Loesch ◽  
Miguel Inca-Martinez ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Latin American ◽  
Copy Number ◽  
Disease Onset ◽  
Copy Number Variants ◽  
Copy Number Variant ◽  
Disease Genes ◽  
Genome Wide ◽  
A Genome

Background: Parkinson's disease is the second most common neurodegenerative disorder and affects people from all ethnic backgrounds, yet little is known about the genetics of Parkinson's disease in non-European populations. In addition, the overall identification of copy number variants at a genome-wide level has been understudied in Parkinson's disease patients. Objectives: To understand the genome-wide burden of copy number variants in Latinos and its association with Parkinson's disease. Methods: We used genome-wide genotyping data from 747 Parkinson's disease patients and 632 ancestry matched controls from the Latin American Research Consortium on the Genetics of Parkinson's disease. Results: Genome-wide copy number burden analysis showed no difference between patients vs. controls, whereas patients were significantly enriched for copy number variants overlapping known Parkinson's disease genes compared to controls (Odds Ratio: 3.97 [1.69 - 10.5], P = 0.018). PARK2 showed the strongest copy number burden, with 20 copy number variant carriers. These patients presented an earlier age of disease onset compared to patients with other copy number variants (median age at onset: 31 years vs. 57 years, P = 7.46 x 10-7). Conclusions: We found that Parkinson's disease patients are significantly enriched with copy number variants affecting known Parkinson's disease genes. We also identified that out of 250 patients with early-onset disease, 5.6% carried a copy number variant on PARK2 in our cohort. Our study is the first to analyze genome-wide copy number variants association in Latino Parkinson's disease patients and provides insights about this complex disease in this understudied population.

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