GWASTools: an R/Bioconductor package for quality control and analysis of genome-wide association studies

Gogarten, Stephanie M.; Bhangale, Tushar; Conomos, Matthew P.; Laurie, Cecelia; McHugh, Caitlin; Painter, Ian; Zheng, Xiuwen; Crosslin, David R.; Levine, David; Lumley, Thomas; Nelson, Sarah C.; Rice, Kenneth; Shen, Jess; Swarnkar, Rohit; Weir, Bruce S.; Laurie, Cathy C.

doi:10.1093/bioinformatics/bts610

Cited by 175 publications

(127 citation statements)

References 8 publications

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“…CNVs were determined algorithmically from Illumina HumanHap 550k BeadChip (for the CHD cases) and Illumina 610k-Quad BeadChip data (for the controls) using the programs PennCNV 13 and GWASTools 14 . In brief, CNVs were considered potentially pathogenic after filtering for size (>300kb), PennCNV quality score >100, overlap with genes, and novelty, as previously reported by Carey et al 6 .…”

Section: Methodsmentioning

confidence: 99%

Burden of potentially pathologic copy number variants is higher in children with isolated congenital heart disease and significantly impairs covariate-adjusted transplant-free survival

Kim

Burt

et al. 2016

The Journal of Thoracic and Cardiovascular Surgery

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Objectives Copy number variants (CNVs) are duplications or deletions of genomic regions. Large CNVs are potentially pathogenic and over-represented in children with congenital heart disease (CHD). We sought to determine the frequency of large CNVs in children with isolated CHD and evaluate the relationship of these potentially pathogenic CNVs with transplant-free survival. Methods These cases are derived from a prospective cohort of non-syndromic CHD patients (n=422) ascertained prior to their first surgery. Healthy pediatric controls (n=500) were obtained from the electronic Medical Records and Genetic Epidemiology (eMERGE) Network and CNV frequency was contrasted for CHD cases and controls. CNVs were algorithmically determined, subsequently screened for >95% overlap between two methods, size (>300kb), quality score, overlap with a gene, and novelty (absent from databases of known, benign CNVs), and separately validated with quantitative-PCR. Survival likelihoods were calculated for cases using Cox proportional hazards modeling to evaluate the joint effect of CNV burden and known confounders on transplant-free survival. Results Children with nonsyndromic CHD had a higher burden of potentially pathogenic CNVs compared to pediatric controls (12.1% vs. 5.0%, P=0.00016). Presence of a CNV was associated with significantly decreased transplant-free survival after surgery (HR=3.42, 95% CI: 1.66-7.09, P=0.00090) with confounder adjustment. Conclusions We confirm that children with isolated CHD have a greater burden of rare/large CNVs. We report a novel finding that these CNVs are associated with an adjusted 2.55-fold increased risk of death or transplant. These data suggest that CNV burden is an important modifier of survival after surgery for CHD.

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Section: Methodsmentioning

confidence: 99%

Burden of potentially pathologic copy number variants is higher in children with isolated congenital heart disease and significantly impairs covariate-adjusted transplant-free survival

Kim

Burt

et al. 2016

The Journal of Thoracic and Cardiovascular Surgery

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“…Ancestry was classified as Black (African-American), White (non-Hispanic Caucasians), Hispanic (Hispanic Caucasian), and others including Asian and multi-racial using GWASTools 12 to generate eigenvalues for the entire dataset.…”

Section: Methodsmentioning

confidence: 99%

Integrated Genomic Analyses in Bronchopulmonary Dysplasia

Ambalavanan¹,

Cotten²,

Page³

et al. 2015

The Journal of Pediatrics

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Objective To identify single nucleotide polymorphisms (SNPs) and pathways associated with bronchopulmonary dysplasia (BPD) because O2 requirement at 36 weeks’ post-menstrual age risk is strongly influenced by heritable factors. Study design A genome-wide scan was conducted on 1.2 million genotyped SNPs, and an additional 7 million imputed SNPs, using a DNA repository of extremely low birth weight infants. Genome-wide association and gene set analysis was performed for BPD or death, severe BPD or death, and severe BPD in survivors. Specific targets were validated using gene expression in BPD lung tissue and in mouse models. Results Of 751 infants analyzed, 428 developed BPD or died. No SNPs achieved genome-wide significance (p<10−8) although multiple SNPs in adenosine deaminase (ADARB2), CD44, and other genes were just below p<10−6. Of approximately 8000 pathways, 75 were significant at False Discovery Rate (FDR) <0.1 and p<0.001 for BPD/death, 95 for severe BPD/death, and 90 for severe BPD in survivors. The pathway with lowest FDR was miR-219 targets (p=1.41E-08, FDR 9.5E-05) for BPD/death and Phosphorous Oxygen Lyase Activity (includes adenylate and guanylate cyclases) for both severe BPD/death (p=5.68E-08, FDR 0.00019) and severe BPD in survivors (p=3.91E-08, FDR 0.00013). Gene expression analysis confirmed significantly increased miR-219 and CD44 in BPD. Conclusions Pathway analyses confirmed involvement of known pathways of lung development and repair (CD44, Phosphorus Oxygen Lyase Activity) and indicated novel molecules and pathways (ADARB2, Targets of miR-219) involved in genetic predisposition to BPD.

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“…The logistic regression model for glioma risk was modeled with a SNP, Sex, SNP × Sex interaction, biospecimen (saliva/blood) and cohort (WU/UTAH/TORONTO/NYU), as well as the first 4 principal components from principal component analysis (PCA) using linkage disequilibrium (LD) pruned SNPs to control for population stratification. The bioConductor package “SNPRelate” (10) was used for LD pruning (the maximum basepairs in the sliding window=10e06, LD threshold=0.2 and the “composite” method was adopted for LD metrics) and PCA analysis and “GWASTools” (11) was used for genome wide association analysis using logistic regression modeling under the dominant genetic model. The odds ratios (ORs) of male, female, ratio of the ORs for glioma risk between males and females (the SNP × Sex interaction) and the likelihood ratio (LR) P-values on the ratio which was obtained by comparing the full logistic regression model to the model leaving the interaction out were reported.…”

Section: Methodsmentioning

confidence: 99%

The Cyclic AMP Pathway Is a Sex-Specific Modifier of Glioma Risk in Type I Neurofibromatosis Patients

et al. 2015

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Identifying modifiers of glioma risk in patients with type 1 neurofibromatosis (NF1) could help support personalized tumor surveillance, advance understanding of gliomagenesis and potentially identify novel therapeutic targets. Here we report genetic polymorphisms in the human adenylate cyclase gene ADCY8 which correlate with glioma risk in NF1 in a sex-specific manner, elevating risk in females while reducing risk in males. This finding extends earlier evidence of a role for cAMP in gliomagenesis based on results in a genetically engineered mouse model (Nf1 GEM). Thus, sexually dimorphic cAMP signaling might render males and females differentially sensitive to variation in cAMP levels. Using male and female Nf1 GEM, we found significant sex differences exist in cAMP regulation and in the growth promoting effects of cAMP suppression. Overall, our results establish a sex-specific role for cAMP regulation in human gliomagenesis, specifically identifying ADCY8 as a modifier of glioma risk in NF1.

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GWASTools: an R/Bioconductor package for quality control and analysis of genome-wide association studies

Cited by 175 publications

References 8 publications

Burden of potentially pathologic copy number variants is higher in children with isolated congenital heart disease and significantly impairs covariate-adjusted transplant-free survival

Burden of potentially pathologic copy number variants is higher in children with isolated congenital heart disease and significantly impairs covariate-adjusted transplant-free survival

Integrated Genomic Analyses in Bronchopulmonary Dysplasia

The Cyclic AMP Pathway Is a Sex-Specific Modifier of Glioma Risk in Type I Neurofibromatosis Patients

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