Estimating Genome‐Wide Significance for Whole‐Genome Sequencing Studies

While atrial fibrillation (AF) is common and has serious consequences, a lot is yet unknown about the causative factors underlying this arrhythmia. The role of genetics in the development of AF has become more evident in the past decade. Family history is now a firmly established risk factor and many common and rare sequence variants linked to AF have been identified. Genome-wide association studies have identified common sequence variants that associate with AF, including variants on chromosomes 4q25, 16q22, and 1q22. Nevertheless, it has become apparent that despite these findings, a substantial fraction of heritability of most complex traits remained unaccounted for. This raises the possibility that development of AF is determined by the combination of common and rare susceptibility variants. Whole genome sequencing is the most comprehensive method to analyse individual genetic variation. A paradigm shift from microarray-based genotyping studies to whole exome and whole genome sequencing is ongoing. Whole genome sequencing studies have shown mutations in myosin genes may be associated with AF, implying that variants encoding sarcomere genes may be involved in the development of this arrhythmia. While some of the sequence variants discovered suggest novel mechanisms in the pathophysiology of this complex arrhythmia, much work is still needed to fully understand the mechanisms linking many of these loci to AF. Likewise, the current clinical applicability of this information is still unclear. However, further developments in this field are expected to add to our understanding of this complex arrhythmia and hopefully lead to new therapeutic possibilities.

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Genome-wide association study using whole-genome sequencing to identify a novel locus associated with cardiomyopathy risk in adult survivors of childhood cancer: Utility of a two-stage analytic approach.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.1516 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 1516-1516

Author(s):

Yadav Sapkota ◽

Qi Liu ◽

Kyla C. Shelton ◽

Xuexia Wang ◽

Carmen Louise Wilson ◽

...

Keyword(s):

Cancer Survivors ◽

Childhood Cancer ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Childhood Cancer Survivors ◽

Whole Genome ◽

Genome Wide ◽

Increased Risk ◽

Survivors Of Childhood Cancer ◽

Genome Wide Significance

1516 Background: Survivors of childhood cancer are at increased risk of treatment-related cardiomyopathy, found to be modified by genetic factors. To further investigate genetic risks of cardiomyopathy, we utilized whole-genome sequencing (WGS) in a clinically phenotyped cohort of long-term survivors of pediatric cancer. Methods: Utilizing a novel 2-stage analytic approach, we first performed association analysis for ejection fraction (EF) using WGS data in European-descent childhood cancer survivors from the St. Jude Lifetime Cohort (SJLIFE). EF was analyzed as a continuous variable to increase statistical power for genetic discovery. Common variants (minor allele frequency (MAF) > 0.05) were analyzed using linear regression, adjusting for age at diagnosis, sex, age at follow-up, doses of anthracycline and average radiation dose to the heart, and eigenvectors. Rare/low-frequency variants were aggregated by different functional annotations and agnostic 4-kb sliding windows, testing jointly using Burden/SKAT test. In the second stage, only the variant showing genome-wide significance with EF was tested for its association with cardiomyopathy risk. Results: Among the 2,015 SJLIFE survivors with WGS data, a locus on 6p21.2 near KCNK17achieved genome-wide significance with EF (rs2815063; MAF = 0.13; per allele beta = -0.016; P = 2.10´10-8), which replicated in 320 SJLIFE African survivors (MAF = 0.48; beta = -0.015; P = 0.004). In SJLIFE Europeans, 282 had a CTCAE Grade 2-5 cardiomyopathy. rs2815063 was significantly associated with increased risk of cardiomyopathy [per allele odds ratio (OR) = 1.38; P = 0.02], which replicated in 3,957 European survivors from the Childhood Cancer Survivor Study (163 CTCAE Grade 3-5 self-reported cases; per allele OR = 1.39; P = 0.038). rs2815063 alters DNA binding motif of EWSR1-FLI1, whose expression was found to lead to cardiomyopathy and death due to chronic cardiac failure in mice. Conclusions: Using a 2-stage approach, we report a novel locus for cardiomyopathy in childhood cancer survivors, which warrants additional work to gain mechanistic insights.

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Integration of genome wide association studies and whole genome sequencing provides novel insights into fat deposition in chicken

Scientific Reports ◽

10.1038/s41598-018-34364-0 ◽

2018 ◽

Vol 8 (1) ◽

Cited By ~ 8

Author(s):

Gabriel Costa Monteiro Moreira ◽

Clarissa Boschiero ◽

Aline Silva Mello Cesar ◽

James M. Reecy ◽

Thaís Fernanda Godoy ◽

...

Keyword(s):

Whole Genome Sequencing ◽

Genome Sequencing ◽

Association Studies ◽

Fat Deposition ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Whole Genome ◽

Genome Wide

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

10.1101/786962 ◽

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.

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BIOM-23. A PILOT STUDY OF WHOLE GENOME SEQUENCING (WGS) OF PLASMA CELL-FREE DNA (cfDNA) FOR ULTRASENSITIVE DETECTION OF TUMOR DNA IN PATIENTS WITH GLIOBLASTOMA (GBM)

Neuro-Oncology ◽

10.1093/neuonc/noab196.054 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi15-vi15

Author(s):

Stephen J Bagley ◽

Jacob Till ◽

Aseel Abdalla ◽

MacLean Nasrallah ◽

Tomer Lauterman ◽

...

Keyword(s):

Pilot Study ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Tumor Tissue ◽

Methylation Status ◽

Tumor Burden ◽

Whole Genome ◽

Newly Diagnosed ◽

Genome Wide ◽

Tumor Dna

Abstract BACKGROUND Plasma circulating tumor DNA (ctDNA) is rarely detectable by traditional methods in patients with GBM. As a result, unlike in lung and other cancers, serial next generation sequencing of ctDNA for monitoring GBM tumor burden has been challenging. In light of the low tumor fraction (TF) of DNA fragments in GBM patient plasma and the urgent need to improve upon MRI for tracking GBM tumor burden, we conducted a pilot study in patients with newly diagnosed GBM using the C2 intelligence platform (C2i Genomics), which leverages genome-wide mutational integration for highly sensitive ctDNA detection. METHODS Plasma was collected pre- and post-operatively in patients with newly diagnosed GBM undergoing surgical resection/biopsy. cfDNA was extracted, quantified, and analyzed for fragment size. Genomic DNA (gDNA) was extracted from matched tumor tissue. Whole genome sequencing (WGS) was performed on both gDNA and cfDNA. A specific copy number alteration (CNA) compendium was created for each patient to generate a readout of TF (Zviran, Nat Medicine 2020). We assessed the association between TF at post-operative day 1 (a surrogate for residual disease) and OS, adjusting for other prognostic factors using Cox regression. RESULTS 37 patients were enrolled. For samples with high tumor fraction (n=5), a statistically significant (p< 1e-4) correlation between CNA profiles of tumor tissue and plasma samples was observed. Post-operative TF above the median value was associated with inferior OS (median 7.7 vs. 19.3 months, p=0.019). This association persisted after adjusting for age, O6-methylguanine-DNA methyltransferase methylation status, extent of resection, and performance status (adjusted HR 2.5, 95% CI 1.1-5.6, p=0.03). CONCLUSION Genome-wide mutational integration enables ultra-sensitive detection of ctDNA in GBM patient plasma. Post-operative TF measured by the C2i test is independently associated with OS in newly diagnosed GBM, providing the foundation to evaluate this technology for personalized prognostication and disease monitoring.

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Candidate Predisposition Variants in Kaposi Sarcoma as Detected by Whole-Genome Sequencing

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz337 ◽

2019 ◽

Vol 6 (10) ◽

Author(s):

Sanni J Rinne ◽

Lauri J Sipilä ◽

Päivi Sulo ◽

Emmanuelle Jouanguy ◽

Vivien Béziat ◽

...

Keyword(s):

Whole Genome Sequencing ◽

Genome Sequencing ◽

Kaposi Sarcoma ◽

The Other ◽

Whole Genome ◽

Genome Wide ◽

Starting Point ◽

Familial Clustering ◽

Iranian Family ◽

Classic Kaposi Sarcoma

Abstract Familial clustering of classic Kaposi sarcoma (CKS) is rare with, approximately 100 families reported to date. We studied 2 consanguineous families, 1 Iranian and 1 Israeli, with multiple cases of adult CKS and without overt underlying immunodeficiency. We performed genome-wide linkage analysis and whole-genome sequencing to discover the putative genetic cause for predisposition. A 9-kb homozygous intronic deletion in RP11-259O2.1 in the Iranian family and 2 homozygous variants, 1 in SCUBE2 and the other in CDHR5, in the Israeli family were identified as possible candidates. The presented variants provide a robust starting point for validation in independent samples.

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Genome‐wide association analyses based on whole‐genome sequencing of Protosalanx hyalocranius provide insights into sex determination of Salangid fishes

Molecular Ecology Resources ◽

10.1111/1755-0998.13172 ◽

2020 ◽

Vol 20 (4) ◽

pp. 1038-1049 ◽

Cited By ~ 2

Author(s):

Yu‐Long Li ◽

Teng‐Fei Xing ◽

Jin‐Xian Liu

Keyword(s):

Sex Determination ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Genome Wide Association ◽

Whole Genome ◽

Association Analyses ◽

Genome Wide

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Fine Mapping Using Whole-Genome Sequencing Confirms Anti-Müllerian Hormone as a Major Gene for Sex Determination in Farmed Nile Tilapia (Oreochromis niloticus L.)

G3 Genes|Genome|Genetics ◽

10.1534/g3.119.400297 ◽

2019 ◽

Vol 9 (10) ◽

pp. 3213-3223 ◽

Cited By ~ 8

Author(s):

Giovanna Cáceres ◽

María E. López ◽

María I. Cádiz ◽

Grazyella M. Yoshida ◽

Ana Jedlicki ◽

...

Keyword(s):

Sex Determination ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Oreochromis Niloticus ◽

Nile Tilapia ◽

Major Gene ◽

Whole Genome ◽

Important Species ◽

Genome Wide ◽

A Genome

Nile tilapia (Oreochromis niloticus) is one of the most cultivated and economically important species in world aquaculture. Intensive production promotes the use of monosex animals, due to an important dimorphism that favors male growth. Currently, the main mechanism to obtain all-male populations is the use of hormones in feeding during larval and fry phases. Identifying genomic regions associated with sex determination in Nile tilapia is a research topic of great interest. The objective of this study was to identify genomic variants associated with sex determination in three commercial populations of Nile tilapia. Whole-genome sequencing of 326 individuals was performed, and a total of 2.4 million high-quality bi-allelic single nucleotide polymorphisms (SNPs) were identified after quality control. A genome-wide association study (GWAS) was conducted to identify markers associated with the binary sex trait (males = 1; females = 0). A mixed logistic regression GWAS model was fitted and a genome-wide significant signal comprising 36 SNPs, spanning a genomic region of 536 kb in chromosome 23 was identified. Ten out of these 36 genetic variants intercept the anti-Müllerian (Amh) hormone gene. Other significant SNPs were located in the neighboring Amh gene region. This gene has been strongly associated with sex determination in several vertebrate species, playing an essential role in the differentiation of male and female reproductive tissue in early stages of development. This finding provides useful information to better understand the genetic mechanisms underlying sex determination in Nile tilapia.

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