TEGS-CN: A Statistical Method for Pathway Analysis of Genome-wide Copy Number Profile

The effects of copy number alterations make up a significant part of the tumor genome profile, but pathway analyses of these alterations are still not well established. We proposed a novel method to analyze multiple copy numbers of genes within a pathway, termed Test for the Effect of a Gene Set with Copy Number data (TEGS-CN). TEGS-CN was adapted from TEGS, a method that we previously developed for gene expression data using a variance component score test. With additional development, we extend the method to analyze DNA copy number data, accounting for different sizes and thus various numbers of copy number probes in genes. The test statistic follows a mixture of X 2 distributions that can be obtained using permutation with scaled X 2 approximation. We conducted simulation studies to evaluate the size and the power of TEGS-CN and to compare its performance with TEGS. We analyzed a genome-wide copy number data from 264 patients of non-small-cell lung cancer. With the Molecular Signatures Database (MSigDB) pathway database, the genome-wide copy number data can be classified into 1814 biological pathways or gene sets. We investigated associations of the copy number profile of the 1814 gene sets with pack-years of cigarette smoking. Our analysis revealed five pathways with significant P values after Bonferroni adjustment (<2.8 x 10-5), including the PTEN pathway (7.8 x 10-7), the gene set up-regulated under heat shock (3.6 x 10-6), the gene sets involved in the immune profile for rejection of kidney transplantation (9.2 x 10-6) and for transcriptional control of leukocytes (2.2 x 10-5), and the ganglioside biosynthesis pathway (2.7 x 10-5). In conclusion, we present a new method for pathway analyses of copy number data, and causal mechanisms of the five pathways require further study.

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Genome-wide association study of treatment-resistance in depression and meta-analysis of three independent samples

The British Journal of Psychiatry ◽

10.1192/bjp.2018.256 ◽

2018 ◽

Vol 214 (1) ◽

pp. 36-41 ◽

Cited By ~ 13

Author(s):

Chiara Fabbri ◽

Siegfried Kasper ◽

Alexander Kautzky ◽

Lucie Bartova ◽

Markus Dold ◽

...

Keyword(s):

Genome Wide Association Study ◽

Meta Analysis ◽

Adenosine Monophosphate ◽

Research Support ◽

Antidepressant Treatments ◽

Advisory Boards ◽

Gene Sets ◽

Genome Wide ◽

A Genome ◽

Resistant Depression

BackgroundTreatment-resistant depression (TRD) is the most problematic outcome of depression in terms of functional impairment, suicidal thoughts and decline in physical health.AimsTo investigate the genetic predictors of TRD using a genome-wide approach to contribute to the development of precision medicine.MethodA sample recruited by the European Group for the Study of Resistant Depression (GSRD) including 1148 patients with major depressive disorder (MDD) was characterised for the occurrence of TRD (lack of response to at least two adequate antidepressant treatments) and genotyped using the Infinium PsychArray. Three clinically relevant patient groups were considered: TRD, responders and non-responders to the first antidepressant trial, thus outcomes were based on comparisons of these groups. Genetic analyses were performed at the variant, gene and gene-set (i.e. functionally related genes) level. Additive regression models of the outcomes and relevant covariates were used in the GSRD participants and in a fixed-effect meta-analysis performed between GSRD, STAR*D (n = 1316) and GENDEP (n = 761) participants.ResultsNo individual polymorphism or gene was associated with TRD, although some suggestive signals showed enrichment in cytoskeleton regulation, transcription modulation and calcium signalling. Two gene sets (GO:0043949 and GO:0000183) were associated with TRD versus response and TRD versus response and non-response to the first treatment in the GSRD participants and in the meta-analysis, respectively (corrected P = 0.030 and P = 0.027).ConclusionsThe identified gene sets are involved in cyclic adenosine monophosphate mediated signal and chromatin silencing, two processes previously implicated in antidepressant action. They represent possible biomarkers to implement personalised antidepressant treatments and targets for new antidepressants.Declaration of interestD.S. has received grant/research support from GlaxoSmithKline and Lundbeck; has served as a consultant or on advisory boards for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen and Lundbeck. S.M. has been a consultant or served on advisory boards for: AstraZeneca, Bristol-Myers Squibb, Forest, Johnson & Johnson, Leo, Lundbeck, Medelink, Neurim, Pierre Fabre, Richter. S.K. has received grant/research support from Eli Lilly, Lundbeck, Bristol-Myers Squibb, GlaxoSmithKline, Organon, Sepracor and Servier; has served as a consultant or on advisory boards for AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly, Lundbeck, Pfizer, Organon, Schwabe, Sepracor, Servier, Janssen and Novartis; and has served on speakers' bureaus for AstraZeneca, Eli Lily, Lundbeck, Schwabe, Sepracor, Servier, Pierre Fabre, Janssen and Neuraxpharm. J.Z. has received grant/research support from Lundbeck, Servier, Brainsway and Pfizer, has served as a consultant or on advisory boards for Servier, Pfizer, Abbott, Lilly, Actelion, AstraZeneca and Roche and has served on speakers' bureaus for Lundbeck, Roch, Lilly, Servier, Pfizer and Abbott. J.M. is a member of the Board of the Lundbeck International Neuroscience Foundation and of Advisory Board of Servier. A.S. is or has been consultant/speaker for: Abbott, AbbVie, Angelini, Astra Zeneca, Clinical Data, Boehringer, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Innovapharma, Italfarmaco, Janssen, Lundbeck, Naurex, Pfizer, Polifarma, Sanofi and Servier. C.M.L. receives research support from RGA UK Services Limited.

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Copy-number variation in sporadic amyotrophic lateral sclerosis: a genome-wide screen

The Lancet Neurology ◽

10.1016/s1474-4422(08)70048-6 ◽

2008 ◽

Vol 7 (4) ◽

pp. 319-326 ◽

Cited By ~ 70

Author(s):

Hylke M Blauw ◽

Jan H Veldink ◽

Michael A van Es ◽

Paul W van Vught ◽

Christiaan GJ Saris ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Copy Number Variation ◽

Copy Number ◽

Sporadic Amyotrophic Lateral Sclerosis ◽

Genome Wide ◽

A Genome ◽

Number Variation ◽

Lateral Sclerosis

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Genome-wide characterization of copy number variations in the host genome in genetic resistance to Marek's disease using next generation sequencing

10.21203/rs.2.12741/v2 ◽

2020 ◽

Author(s):

Hao Bai ◽

Yanghua He ◽

Yi Ding ◽

Huanmin Zhang ◽

Jilan Chen ◽

...

Keyword(s):

Next Generation Sequencing ◽

Copy Number ◽

Marek's Disease ◽

Neoplastic Disease ◽

Marek’S Disease ◽

Next Generation ◽

Qrt Pcr ◽

Genome Wide ◽

A Genome ◽

Generation Sequencing

Abstract Background: Marek’s disease (MD) is a highly neoplastic disease primarily affecting chickens, and remains as a chronic infectious disease that threatens the poultry industry. Copy number variation (CNV) has been examined in many species and is recognized as a major source of genetic variation that directly contributes to phenotypic variation such as resistance to infectious diseases. Two highly inbred chicken lines 63 (MD-resistant) and 72 (MD-susceptible), as well as their F1 generation and six recombinant congenic strains (RCSs) with varied susceptibility to MD, are considered as ideal models to identify the complex mechanisms of genetic and molecular resistance to MD.Results: In the present study, to unravel the potential genetic mechanisms underlying resistance to MD, we performed a genome-wide CNV detection using next generation sequencing on the inbred chicken lines with the assistance of CNVnator. As a result, a total of 1,649 CNV regions (CNVRs) were successfully identified after merging all the nine datasets, of which 90 CNVRs were overlapped across all the chicken lines. Within these shared regions, 1,360 harbored genes were identified. In addition, 55 and 44 CNVRs with 62 and 57 harbored genes were specifically identified in line 63 and 72, respectively. Bioinformatics analysis showed that the nearby genes were significantly enriched in 36 GO terms and 6 KEGG pathways including JAK/STAT signaling pathway. Ten CNVRs (nine deletions and one duplication) involved in 10 disease-related genes were selected for validation by using qRT-PCR, all of which were successfully confirmed. Finally, qRT-PCR was also used to validate two deletion events in line 72 that were definitely normal in line 63. One high-confidence gene, IRF2 was identified as the most promising candidate gene underlying resistance and susceptibility to MD in view of its function and overlaps with data from previous study.Conclusions: Our findings provide valuable insights for understanding the genetic mechanism of resistance to MD and the identified gene and pathway could be considered as the subject of further functional characterization.

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A genome-wide survey of copy number variation regions in various chicken breeds by array comparative genomic hybridization method

Animal Genetics ◽

10.1111/j.1365-2052.2011.02308.x ◽

2012 ◽

Vol 43 (3) ◽

pp. 282-289 ◽

Cited By ~ 26

Author(s):

Y. Wang ◽

X. Gu ◽

C. Feng ◽

C. Song ◽

X. Hu ◽

...

Keyword(s):

Copy Number Variation ◽

Copy Number ◽

Array Comparative Genomic Hybridization ◽

Comparative Genomic ◽

Hybridization Method ◽

Genome Wide ◽

A Genome ◽

Number Variation ◽

Chicken Breeds ◽

Genome Wide Survey

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A genome-wide analysis of copy number variation in Murciano-Granadina goats

Genetics Selection Evolution ◽

10.1186/s12711-020-00564-4 ◽

2020 ◽

Vol 52 (1) ◽

Author(s):

Dailu Guan ◽

Amparo Martínez ◽

Anna Castelló ◽

Vincenzo Landi ◽

María Gracia Luigi-Sierra ◽

...

Keyword(s):

Copy Number Variation ◽

Copy Number ◽

Genome Wide Analysis ◽

Genome Wide ◽

A Genome ◽

Number Variation

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

Journal of Clinical Medicine ◽

10.3390/jcm8030332 ◽

2019 ◽

Vol 8 (3) ◽

pp. 332 ◽

Cited By ~ 4

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.

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Weighted Kolmogorov Smirnov testing: an alternative for Gene Set Enrichment Analysis

Statistical Applications in Genetics and Molecular Biology ◽

10.1515/sagmb-2014-0077 ◽

2015 ◽

Vol 14 (3) ◽

Cited By ~ 13

Author(s):

Konstantina Charmpi ◽

Bernard Ycart

Keyword(s):

Weight Function ◽

Null Hypothesis ◽

Computing Time ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Test Statistic ◽

Gene Set Enrichment ◽

Gene Set ◽

Gene Sets ◽

Kolmogorov Smirnov

AbstractGene Set Enrichment Analysis (GSEA) is a basic tool for genomic data treatment. Its test statistic is based on a cumulated weight function, and its distribution under the null hypothesis is evaluated by Monte-Carlo simulation. Here, it is proposed to subtract to the cumulated weight function its asymptotic expectation, then scale it. Under the null hypothesis, the convergence in distribution of the new test statistic is proved, using the theory of empirical processes. The limiting distribution needs to be computed only once, and can then be used for many different gene sets. This results in large savings in computing time. The test defined in this way has been called Weighted Kolmogorov Smirnov (WKS) test. Using expression data from the GEO repository, tested against the MSig Database C2, a comparison between the classical GSEA test and the new procedure has been conducted. Our conclusion is that, beyond its mathematical and algorithmic advantages, the WKS test could be more informative in many cases, than the classical GSEA test.

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A Genome-Wide Association Study to Identify Potential Germline Copy Number Variants for Sporadic Breast Cancer Susceptibility

Cytogenetic and Genome Research ◽

10.1159/000448558 ◽

2016 ◽

Vol 149 (3) ◽

pp. 156-164 ◽

Cited By ~ 2

Author(s):

Yadav Sapkota ◽

Ashok Narasimhan ◽

Mahalakshmi Kumaran ◽

Badan S. Sehrawat ◽

Sambasivarao Damaraju

Keyword(s):

Breast Cancer ◽

Association Study ◽

Copy Number ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Frequency Effect ◽

Potential Candidate ◽

Disease Etiology ◽

Genome Wide ◽

A Genome

Breast cancer (BC) predisposition in populations arises from both genetic and nongenetic risk factors. Structural variations such as copy number variations (CNVs) are heritable determinants for disease susceptibility. The primary objectives of this study are (1) to identify CNVs associated with sporadic BC using a genome-wide association study (GWAS) design; (2) to utilize 2 distinct CNV calling algorithms to identify concordant CNVs as a strategy to reduce false positive associations in the hypothesis-generating GWAS discovery phase, and (3) to identify potential candidate CNVs for follow-up replication studies. We used Affymetrix SNP Array 6.0 data profiled on Caucasian subjects (422 cases/348 controls) to call CNVs using algorithms implemented in Nexus Copy Number and Partek Genomics Suite software. Nexus algorithm identified CNVs associated with BC (731 autosomal CNVs with >5% frequency in the total sample and Q < 0.05). Thirteen CNVs were identified when Partek algorithm-called CNVs were overlapped with Nexus-identified CNVs; these CNVs showed concordances for frequency, effect size, and direction. Coding genes present within BC-associated CNVs were known to play a role in disease etiology and prognosis. Long noncoding RNAs identified within CNVs showed tissue-specific expression, indicating potential functional relevance of the findings. The identified candidate CNVs warrant independent replication.

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