scholarly journals Genes identified through genome-wide association studies of osteonecrosis in childhood acute lymphoblastic leukemia patients

2019 ◽  
Vol 20 (17) ◽  
pp. 1189-1197 ◽  
Author(s):  
Vincent Gagné ◽  
Anne Aubry-Morin ◽  
Maria Plesa ◽  
Rachid Abaji ◽  
Kateryna Petrykey ◽  
...  
Keyword(s):  
Association Studies ◽  
Lymphoblastic Leukemia ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Sequencing Data ◽  
Childhood All ◽  
Exome Sequencing Data ◽  
Genome Wide ◽  
Whole Exome ◽  
Whole Exome Sequencing Data

Aim: To evaluate top-ranking genes identified through genome-wide association studies for an association with corticosteroid-related osteonecrosis in children with acute lymphoblastic leukemia (ALL) who received Dana–Farber Cancer Institute treatment protocols. Patients & methods: Lead SNPs from these studies, as well as other variants in the same genes, pooled from whole exome sequencing data, were analyzed for an association with osteonecrosis in childhood ALL patients from Quebec cohort. Top-ranking variants were verified in the replication patient group. Results: The analyses of variants in the ACP1-SH3YL1 locus derived from whole exome sequencing data showed an association of several correlated SNPs (rs11553746, rs2290911, rs7595075, rs2306060 and rs79716074). The rs79716074 defines *B haplotype of the APC1 gene, which is well known for its functional role. Conclusion: This study confirms implication of the ACP1 gene in the treatment-related osteonecrosis in childhood ALL and identifies novel, potentially causal variant of this complication.

scholarly journals Genome-wide discovery of epistatic loci affecting antibiotic resistance using evolutionary couplings

2018 ◽  
Author(s):  
Benjamin Schubert ◽  
Rohan Maddamsetti ◽  
Jackson Nyman ◽  
Maha R. Farhat ◽  
Debora S. Marks
Keyword(s):  
Antibiotic Resistance ◽  
Statistical Power ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Genome Wide Association ◽  
Whole Genome Sequencing Data ◽  
Genome Wide Association Studies ◽  
Sequencing Data ◽  
Vast Number ◽  
Genome Wide

ABSTRACTThe analysis of whole genome sequencing data should, in theory, allow the discovery of interdependent loci that cause antibiotic resistance. In practice, however, identifying this epistasis remains a challenge as the vast number of possible interactions erodes statistical power. To solve this problem, we extend a method that has been successfully used to identify epistatic residues in proteins to infer genomic loci that are strongly coupled and associated with antibiotic resistance. Our method reduces the number of tests required for an epistatic genome-wide association study and increases the likelihood of identifying causal epistasis. We discovered 38 loci and 250 epistatic pairs that influence the dose needed to inhibit growth for five different antibiotics in 1,102 isolates of Neisseria gonorrhoeae that were confirmed in an independent dataset of 495 isolates. Many known resistance-affecting loci were recovered; however, the majority of loci occurred in unreported genes, including murE which was associated with cefixime. About half of the novel epistasis we report involved at least one locus previously associated with antibiotic resistance, including interactions between gyrA and parC associated with ciprofloxacin. Still, many combinations involved unreported loci and genes. Our work provides a systematic identification of epistasis pairs affecting antibiotic resistance in N. gonorrhoeae and a generalizable method for epistatic genome-wide association studies.

scholarly journals Inherited genetic variation in childhood acute lymphoblastic leukemia

Blood ◽  
2015 ◽  
Vol 125 (26) ◽  
pp. 3988-3995 ◽  
Author(s):  
Takaya Moriyama ◽  
Mary V. Relling ◽  
Jun J. Yang
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Association Studies ◽  
Lymphoblastic Leukemia ◽  
Genetic Variations ◽  
Host Susceptibility ◽  
Genome Wide Association Studies ◽  
Childhood All ◽  
Germline Variants ◽  
Complex Interactions ◽  
Genome Wide

Abstract Although somatically acquired genomic alterations have long been recognized as the hallmarks of acute lymphoblastic leukemia (ALL), the last decade has shown that inherited genetic variations (germline) are important determinants of interpatient variability in ALL susceptibility, drug response, and toxicities of ALL therapy. In particular, unbiased genome-wide association studies have identified germline variants strongly associated with the predisposition to ALL in children, providing novel insight into the mechanisms of leukemogenesis and evidence for complex interactions between inherited and acquired genetic variations in ALL. Similar genome-wide approaches have also discovered novel germline genetic risk factors that independently influence ALL prognosis and those that strongly modify host susceptibility to adverse effects of antileukemic agents (eg, vincristine, asparaginase, glucocorticoids). There are examples of germline genomic associations that warrant routine clinical use in the treatment of childhood ALL (eg, TPMT and mercaptopurine dosing), but most have not reached this level of actionability. Future studies are needed to integrate both somatic and germline variants to predict risk of relapse and host toxicities, with the eventual goal of implementing genetics-driven precision-medicine approaches in ALL treatment.

scholarly journals HLA alleles associated with asparaginase hypersensitivity in childhood ALL: a report from the DFCI Consortium

2020 ◽  
Vol 21 (8) ◽  
pp. 541-547 ◽  
Author(s):  
Vincent Gagné ◽  
Pascal St-Onge ◽  
Patrick Beaulieu ◽  
Caroline Laverdière ◽  
Jean-Marie Leclerc ◽  
...  
Keyword(s):  
Lymphoblastic Leukemia ◽  
Human Leukocyte ◽  
Sequencing Data ◽  
Treatment Protocols ◽  
Childhood All ◽  
Hla Alleles ◽  
Leukocyte Antigen ◽  
Whole Exome ◽  
Whole Exome Sequencing Data ◽  
Hla Dqa1

Aim: To evaluate the association between human leukocyte antigen (HLA) alleles and native Escherichia coli asparaginase hypersensitivity (AH) in children with acute lymphoblastic leukemia (ALL) who received Dana-Farber Cancer Institute treatment protocols. Patients & methods: HLA-DQA1, HLA-DRB1 and HLA-DQB1 alleles were retrieved from available whole exome sequencing data of a subset of childhood ALL patients from Quebec ALL cohort and analyzed for an association with AH. PCR assay was developed to analyze associated alleles in the entire discovery and replication cohorts. Results: Two alleles in linkage disequilibrium ( HLA-DRB1*07:01 and DQA1*02:01) were associated with AH. Additional analyses, performed to distinguish between HLA-DRB1*07:01 haplotypes with and without DQB1*02:02 allele, showed that the association was dependent on the presence of DQB1*02:02. Conclusion: This study confirms the implication of HLA-DRB1*07:01, DQA1*02:01 and DQB1*02:02 alleles in developing AH in childhood ALL.

scholarly journals Identification of deleterious and regulatory genomic variations in known asthma loci

2018 ◽  
Author(s):  
Matthew D. C. Neville ◽  
Jihoon Choi ◽  
Jonathan Lieberman ◽  
Qing Ling Duan
Keyword(s):  
Candidate Gene ◽  
Association Studies ◽  
Genome Wide Association ◽  
Whole Genome Sequencing Data ◽  
Sequence Variants ◽  
Genome Wide Association Studies ◽  
Sequencing Data ◽  
Regulatory Variants ◽  
Genome Wide ◽  
Regulatory Effects

AbstractBackgroundCandidate gene and genome-wide association studies have identified hundreds of asthma risk loci. The majority of associated variants, however, are not known to have any biological function and are believed to represent markers rather than true causative mutations. We hypothesized that many of these associated markers are in linkage disequilibrium (LD) with the elusive causative variants.MethodsWe compiled a comprehensive list of 447 asthma-associated variants previously reported in candidate gene and genome-wide association studies. Next, we identified all sequence variants located within the 304 unique genes using whole-genome sequencing data from the 1000 Genomes Project. Then, we calculated the LD between known asthma variants and the sequence variants within each gene. LD variants identified were then annotated to determine those that are potentially deleterious and/or functional (i.e. coding or regulatory effects on the encoded transcript or protein).ResultsWe identified 10,048 variants in LD (r2 > 0.6) with known asthma variants. Annotations of these LD variants revealed that several have potentially deleterious effects including frameshift, alternate splice site, stop-lost, and missense. Moreover, 24 of the LD variants have been reported to regulate gene expression as expression quantitative trait loci (eQTLs).ConclusionsThis study is proof of concept that many of the genetic loci previously associated with complex diseases such as asthma are not causative but represent markers of disease, which are in LD with the elusive causative variants. We hereby report a number of potentially deleterious and regulatory variants that are in LD with the reported asthma loci. These reported LD variants could account for the original association signals with asthma and represent the true causative mutations at these loci.

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