scholarly journals Common Variation in Cytoskeletal Genes Is Associated with Conotruncal Heart Defects

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 655
Author(s):  
Fadi I. Musfee ◽  
A. J. Agopian ◽  
Elizabeth Goldmuntz ◽  
Hakon Hakonarson ◽  
Bernice E. Morrow ◽  
...  
Keyword(s):  
Candidate Gene ◽  
Heart Defects ◽  
Left Ventricular ◽  
Gene Set ◽  
Common Variation ◽  
Conotruncal Heart Defects ◽  
Gene Sets ◽  
Genome Wide ◽  
Common Genetic Variants ◽  
Using Data

There is strong evidence for a genetic contribution to non-syndromic congenital heart defects (CHDs). However, exome- and genome-wide studies conducted at the variant and gene-level have identified few genome-wide significant CHD-related genes. Gene-set analyses are a useful complement to such studies and candidate gene-set analyses of rare variants have provided insight into the genetics of CHDs. However, similar analyses have not been conducted using data on common genetic variants. Consequently, we conducted common variant analyses of 15 CHD candidate gene-sets, using data from two common types of CHDs: conotruncal heart defects (1431 cases) and left ventricular outflow tract defects (509 cases). After Bonferroni correction for evaluation of multiple gene-sets, the cytoskeletal gene-set was significantly associated with conotruncal heart defects (βS = 0.09; 95% confidence interval (CI) 0.03–0.15). This association was stronger when analyses were restricted to the sub-set of cytoskeletal genes that have been observed to harbor rare damaging genotypes in at least two CHD cases (βS = 0.32, 95% CI 0.08–0.56). These findings add to the evidence linking cytoskeletal genes to CHDs and suggest that, for cytoskeletal genes, common variation may contribute to the risk of CHDs.

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

2014 ◽  
Vol 13s4 ◽  
pp. CIN.S13978
Author(s):  
Yen-Tsung Huang ◽  
Thomas Hsu ◽  
David C. Christiani
Keyword(s):  
Copy Number ◽  
Copy Number Data ◽  
Copy Number Profile ◽  
Test Statistic ◽  
Gene Set ◽  
Bonferroni Adjustment ◽  
Gene Sets ◽  
Genome Wide ◽  
A Genome ◽  
Pathway Analyses

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.

scholarly journals Genome-Wide Association Study of Maternal and Inherited Loci for Conotruncal Heart Defects

PLoS ONE ◽  
2014 ◽  
Vol 9 (5) ◽  
pp. e96057 ◽  
Author(s):  
A. J. Agopian ◽  
Laura E. Mitchell ◽  
Joseph Glessner ◽  
Angela D. Bhalla ◽  
Anshuman Sewda ◽  
...  
Keyword(s):  
Association Study ◽  
Genome Wide Association Study ◽  
Heart Defects ◽  
Genome Wide Association ◽  
Conotruncal Heart Defects ◽  
Genome Wide

scholarly journals Novel Ultra-Rare Exonic Variants Identified in a Founder Population Implicate Cadherins in Schizophrenia

2020 ◽  
Author(s):  
Todd Lencz ◽  
Jin Yu ◽  
Raiyan Rashid Khan ◽  
Shai Carmi ◽  
Max Lam ◽  
...  
Keyword(s):  
Rare Variant ◽  
Rare Variants ◽  
Gene List ◽  
Ashkenazi Jewish ◽  
Founder Population ◽  
Total N ◽  
Gene Set ◽  
Complex Disorders ◽  
Gene Sets ◽  
Common Genetic Variants

AbstractIMPORTANCESchizophrenia is a serious mental illness with high heritability. While common genetic variants account for a portion of the heritability, identification of rare variants associated with the disorder has proven challenging.OBJECTIVETo identify genes and gene sets associated with schizophrenia in a founder population (Ashkenazi Jewish), and to determine the relative power of this population for rare variant discovery.DESIGN, SETTING, AND PARTICIPANTSData on exonic variants were extracted from whole genome sequences drawn from 786 patients with schizophrenia and 463 healthy control subjects, all drawn from the Ashkenazi Jewish population. Variants observed in two large publicly available datasets (total n≈153,000, excluding neuropsychiatric patients) were filtered out, and novel ultra-rare variants (URVs) were compared in cases and controls.MAIN OUTCOMES AND MEASURESThe number of novel URVs and genes carrying them were compared across cases and controls. Genes in which only cases or only controls carried novel, functional URVs were examined using gene set analyses.RESULTSCases had a higher frequency of novel missense or loss of function (MisLoF) variants compared to controls, as well as a greater number of genes impacted by MisLoF variants. Characterizing 141 “case-only” genes (in which ≥ 3 AJ cases in our dataset had MisLoF URVs with none found in our AJ controls), we replicated prior findings of both enrichment for synaptic gene sets, as well as specific genes such as SETD1A and TRIO. Additionally, we identified cadherins as a novel gene set associated with schizophrenia including a recurrent mutation in PCDHA3. Several genes associated with autism and other neurodevelopmental disorders including CACNA1E, ASXL3, SETBP1, and WDFY3, were also identified in our case-only gene list, as was TSC2, which is linked to tuberous sclerosis. Modeling the effects of purifying selection demonstrated that deleterious rare variants are greatly over-represented in a founder population with a tight bottleneck and rapidly expanding census, resulting in enhanced power for rare variant association studies.CONCLUSIONS AND RELEVANCEIdentification of cell adhesion genes in the cadherin/protocadherin family is consistent with evidence from large-scale GWAS in schizophrenia, helps specify the synaptic abnormalities that may be central to the disorder, and suggests novel potential treatment strategies (e.g., inhibition of protein kinase C). Study of founder populations may serve as a cost-effective way to rapidly increase gene discovery in schizophrenia and other complex disorders.

scholarly journals Genome-Wide Association Studies of Conotruncal Heart Defects with Normally Related Great Vessels in the United States

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 1030
Author(s):  
Omobola O. Oluwafemi ◽  
Fadi I. Musfee ◽  
Laura E. Mitchell ◽  
Elizabeth Goldmuntz ◽  
Hongbo M. Xie ◽  
...  
Keyword(s):  
Association Studies ◽  
Heart Defects ◽  
22Q11.2 Deletion Syndrome ◽  
The United States ◽  
Deletion Syndrome ◽  
Genome Wide Association Studies ◽  
Gene Set ◽  
Genome Wide ◽  
Gene Level ◽  
Great Vessels

Conotruncal defects with normally related great vessels (CTD-NRGVs) occur in both patients with and without 22q11.2 deletion syndrome (22q11.2DS), but it is unclear to what extent the genetically complex etiologies of these heart defects may overlap across these two groups, potentially involving variation within and/or outside of the 22q11.2 region. To explore this potential overlap, we conducted genome-wide SNP-level, gene-level, and gene set analyses using common variants, separately in each of five cohorts, including two with 22q11.2DS (N = 1472 total cases) and three without 22q11.2DS (N = 935 total cases). Results from the SNP-level analyses were combined in meta-analyses, and summary statistics from these analyses were also used in gene and gene set analyses. Across all these analyses, no association was significant after correction for multiple comparisons. However, several SNPs, genes, and gene sets with suggestive evidence of association were identified. For common inherited variants, we did not identify strong evidence for shared genomic mechanisms for CTD-NRGVs across individuals with and without 22q11.2 deletions. Nevertheless, several of our top gene-level and gene set results have been linked to cardiogenesis and may represent candidates for future work.

scholarly journals Identification of novel candidate gene loci and increased sex chromosome aneuploidy among infants with conotruncal heart defects

2013 ◽  
Vol 164 (2) ◽  
pp. 397-406 ◽  
Author(s):  
Kazutoyo Osoegawa ◽  
David M. Iovannisci ◽  
Bin Lin ◽  
Christina Parodi ◽  
Kathleen Schultz ◽  
...  
Keyword(s):  
Candidate Gene ◽  
Sex Chromosome ◽  
Heart Defects ◽  
Sex Chromosome Aneuploidy ◽  
Conotruncal Heart Defects ◽  
Chromosome Aneuploidy

scholarly journals Gene-based genome-wide association studies and meta-analyses of conotruncal heart defects

PLoS ONE ◽  
2019 ◽  
Vol 14 (7) ◽  
pp. e0219926 ◽  
Author(s):  
Anshuman Sewda ◽  
A. J. Agopian ◽  
Elizabeth Goldmuntz ◽  
Hakon Hakonarson ◽  
Bernice E. Morrow ◽  
...  
Keyword(s):  
Association Studies ◽  
Heart Defects ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Conotruncal Heart Defects ◽  
Genome Wide ◽  
Meta Analyses

scholarly journals Elucidating essential genes in plant-associated Pseudomonas protegens Pf-5 using transposon insertion sequencing

2020 ◽  
Author(s):  
Belinda K Fabian ◽  
Christie Foster ◽  
Amy J Asher ◽  
Liam D. H. Elbourne ◽  
Amy K Cain ◽  
...  
Keyword(s):  
Essential Gene ◽  
Bacterial Pathogens ◽  
Essential Genes ◽  
Associated Bacteria ◽  
Gene Essentiality ◽  
Gene Set ◽  
Transposon Insertion ◽  
Gene Sets ◽  
Genome Wide ◽  
Transposon Insertion Sequencing

Gene essentiality studies have been performed on numerous bacterial pathogens, but essential gene sets have been determined for only a few plant-associated bacteria. Pseudomonas protegens Pf-5 is a plant-commensal, biocontrol bacteria that can control disease-causing pathogens on a wide range of crops. Work on Pf-5 has mostly focused on secondary metabolism and biocontrol genes, but genome-wide approaches such as high-throughput transposon mutagenesis have not yet been used in this species. Here we generated a dense P. protegens Pf-5 transposon mutant library and used transposon-directed insertion site sequencing (TraDIS) to identify 446 genes essential for growth on rich media. Genes required for fundamental cellular machinery were enriched in the essential gene set, while genes related to nutrient biosynthesis, stress responses and transport were under-represented. The majority of Pf-5 essential genes were part of the P. protegens core genome. Comparison of the essential gene set of Pf-5 with those of two plant associated pseudomonads, P. simiae and P. syringae, and the well-studied opportunistic human pathogen P. aeruginosa PA14 showed the four species share a large number of essential genes, but each species also had uniquely essential genes. Comparison of the Pf-5 in silico predicted and in vitro determined essential gene sets highlighted the essential cellular functions that are over- and underestimated by each method. Expanding essentiality studies into bacteria with a range of lifestyles may improve our understanding of the biological processes important for bacterial survival and growth. Importance Essential genes are those crucial for survival or normal growth rates in an organism. Essential gene sets have been identified in numerous bacterial pathogens, but only a few plant-associated bacteria. Employing genome-wide approaches, such as transposon insertion sequencing, allows for the concurrent analysis of all genes of a bacterial species and rapid determination of essential gene sets. We have used transposon insertion sequencing to systematically analyze thousands of Pseudomonas protegens Pf-5 genes and gain insights into gene functions and interactions that are not readily available using traditional methods. Comparing Pf-5 essential genes with those of three other pseudomonads highlights how gene essentiality varies between closely related species.

scholarly journals Integrating Genome-Wide Association and eQTLs Studies Identifies the Genes and Gene Sets Associated with Diabetes

2017 ◽  
Vol 2017 ◽  
pp. 1-4 ◽  
Author(s):  
Xiao Liang ◽  
Awen He ◽  
Wenyu Wang ◽  
Li Liu ◽  
Yanan Du ◽  
...  
Keyword(s):  
Fasting Glucose ◽  
Association Studies ◽  
Integrative Analysis ◽  
Gene Set Enrichment Analysis ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Gene Set ◽  
Gene Sets ◽  
Genome Wide ◽  
Summary Data

Aim. To identify novel candidate genes and gene sets for diabetes. Methods. We performed an integrative analysis of genome-wide association studies (GWAS) and expression quantitative trait loci (eQTLs) data for diabetes. Summary data was driven from a large-scale GWAS of diabetes, totally involving 58,070 individuals. eQTLs dataset included 923,021 cis-eQTL for 14,329 genes and 4,732 trans-eQTL for 2,612 genes. Integrative analysis of GWAS and eQTLs data was conducted by summary data-based Mendelian randomization (SMR). To identify the gene sets associated with diabetes, the SMR single gene analysis results were further subjected to gene set enrichment analysis (GSEA). A total of 13,311 annotated gene sets were analyzed in this study. Results. SMR analysis identified 6 genes significantly associated with fasting glucose, such as C11ORF10 (p value = 6.04 × 10−8), MRPL33 (p value = 1.24 × 10−7), and FADS1 (p value = 2.39 × 10−7). Gene set analysis identified HUANG_FOXA2_TARGETS_UP (false discovery rate = 0.047) associated with fasting glucose. Conclusion. Our study provides novel clues for clarifying the genetic mechanism of diabetes. This study also illustrated the good performance of SMR approach and extended it to gene set association analysis for complex diseases.

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