scholarly journals A genome-wide association study of susceptibility to acute lymphoblastic leukemia in adolescents and young adults

Blood ◽  
2015 ◽  
Vol 125 (4) ◽  
pp. 680-686 ◽  
Author(s):  
Virginia Perez-Andreu ◽  
Kathryn G. Roberts ◽  
Heng Xu ◽  
Colton Smith ◽  
Hui Zhang ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Genetic Basis ◽  
Genome Wide Association Study ◽  
Lymphoblastic Leukemia ◽  
Genome Wide Association ◽  
Age Group ◽  
Genome Wide ◽  
A Genome ◽  
Key Points ◽  
Similarities And Differences

Key Points In this first ALL GWAS in AYAs, we determined that inherited GATA3 variants strongly influence ALL susceptibility in this age group. These findings revealed similarities and differences in the genetic basis of ALL susceptibility between young children and AYAs.

scholarly journals Genome-Wide Association Study of Susceptibility Loci for T-Cell Acute Lymphoblastic Leukemia in Children

2019 ◽  
Vol 111 (12) ◽  
pp. 1350-1357 ◽  
Author(s):  
Maoxiang Qian ◽  
Xujie Zhao ◽  
Meenakshi Devidas ◽  
Wenjian Yang ◽  
Yoshihiro Gocho ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Risk Allele ◽  
Lymphoblastic Leukemia ◽  
Genome Wide Association ◽  
Luciferase Assay ◽  
Susceptibility Loci ◽  
Genome Wide ◽  
A Genome

Abstract Background Acute lymphoblastic leukemia (ALL) is the most common cancer in children and can arise in B or T lymphoid lineages. Although risk loci have been identified for B-ALL, the inherited basis of T-ALL is mostly unknown, with a particular paucity of genome-wide investigation of susceptibility variants in large patient cohorts. Methods We performed a genome-wide association study (GWAS) in 1191 children with T-ALL and 12 178 controls, with independent replication using 117 cases and 5518 controls. The associations were tested using an additive logistic regression model. Top risk variants were tested for effects on enhancer activity using luciferase assay. All statistical tests were two sided. Results A novel risk locus in the USP7 gene (rs74010351, odds ratio [OR] = 1.44, 95% confidence interval [CI] = 1.27 to 1.65, P = 4.51 × 10–8) reached genome-wide significance in the discovery cohort, with independent validation (OR = 1.51, 95% CI = 1.03 to 2.22, P = .04). The USP7 risk allele was overrepresented in individuals of African descent, thus contributing to the higher incidence of T-ALL in this race/ethnic group. Genetic changes in USP7 (germline variants or somatic mutations) were observed in 56.4% of T-ALL with TAL1 overexpression, statistically significantly higher than in any other subtypes. Functional analyses suggested this T-ALL risk allele is located in a putative cis-regulatory DNA element with negative effects on USP7 transcription. Finally, comprehensive comparison of 14 susceptibility loci in T- vs B-ALL pointed to distinctive etiology of these leukemias. Conclusions These findings indicate strong associations between inherited genetic variation and T-ALL susceptibility in children and shed new light on the molecular etiology of ALL, particularly commonalities and differences in the biology of the two major subtypes (B- vs T-ALL).

scholarly journals Genome-Wide Association Study of Susceptibility Loci for TCF3-PBX1 Acute Lymphoblastic Leukemia in Children

2020 ◽  
Author(s):  
Shawn H R Lee ◽  
Maoxiang Qian ◽  
Wentao Yang ◽  
Jonathan D Diedrich ◽  
Elizabeth Raetz ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Molecular Subtype ◽  
Lymphoblastic Leukemia ◽  
Specific Effect ◽  
Genome Wide Association ◽  
Inherited Susceptibility ◽  
Genome Wide ◽  
A Genome

Abstract Acute lymphoblastic leukemia (ALL) is the most common cancer in children. TCF3-PBX1 fusion defines a common molecular subtype of ALL with unique clinical features, but the molecular basis of its inherited susceptibility is unknown. In a genome-wide association study of 1494 ALL cases and 2057 non-ALL controls, we identified a germline risk locus located in an intergenic region between BCL11A and PAPOLG: rs2665658, P = 1.88 × 10–8 for TCF3-PBX1 ALL vs non-ALL, and P = 1.70 × 10–8 for TCF3-PBX1 ALL vs other-ALL. The lead variant was validated in a replication cohort, and conditional analyses pointed to a single causal variant with subtype-specific effect. The risk variant is located in a regulatory DNA element uniquely activated in ALL cells with the TCF3-PBX1 fusion and may distally modulate the transcription of the adjacent gene REL. Our results expand the understanding of subtype-specific ALL susceptibility and highlight plausible interplay between germline variants and somatic genomic abnormalities in ALL pathogenesis.

scholarly journals Clinical and Genetic Risk Factors for Acute Pancreatitis in Patients With Acute Lymphoblastic Leukemia

2016 ◽  
Vol 34 (18) ◽  
pp. 2133-2140 ◽  
Author(s):  
Chengcheng Liu ◽  
Wenjian Yang ◽  
Meenakshi Devidas ◽  
Cheng Cheng ◽  
Deqing Pei ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Pancreatitis ◽  
Native American ◽  
Acute Lymphoblastic Leukemia ◽  
Genetic Risk ◽  
Genome Wide Association Study ◽  
Lymphoblastic Leukemia ◽  
Genome Wide Association ◽  
Common Variants ◽  
Genome Wide

Purpose Acute pancreatitis is one of the common causes of asparaginase intolerance. The mechanism is unknown, and genetic predisposition to asparaginase-induced pancreatitis has not been previously identified. Methods To determine clinical risk factors for asparaginase-induced pancreatitis, we studied a cohort of 5,185 children and young adults with acute lymphoblastic leukemia, including 117 (2.3%) who were diagnosed with at least one episode of acute pancreatitis during therapy. A genome-wide association study was performed in the cohort and in an independent case-control group of 213 patients to identify genetic risk factors. Results Risk factors associated with pancreatitis included genetically defined Native American ancestry (P < .001), older age (P < .001), and higher cumulative dose of asparaginase (P < .001). No common variants reached genome-wide significance in the genome-wide association study, but a rare nonsense variant rs199695765 in CPA2, encoding carboxypeptidase A2, was highly associated with pancreatitis (hazard ratio, 587; 95% CI, 66.8 to 5166; P = 9.0 × 10−9). A gene-level analysis showed an excess of additional CPA2 variants in patients who did versus those who did not develop pancreatitis (P = .001). Sixteen CPA2 single-nucleotide polymorphisms were associated (P < .05) with pancreatitis, and 13 of 24 patients who carried at least one of these variants developed pancreatitis. Biologic functions that were overrepresented by common variants modestly associated with pancreatitis included purine metabolism and cytoskeleton regulation. Conclusion Older age, higher exposure to asparaginase, and higher Native American ancestry were independent risk factors for pancreatitis in patients with acute lymphoblastic leukemia. Those who inherit a nonsense rare variant in the CPA2 gene had a markedly increased risk of asparaginase-induced pancreatitis.

scholarly journals Inherited NUDT15 Variant Is a Genetic Determinant of Mercaptopurine Intolerance in Children With Acute Lymphoblastic Leukemia

2015 ◽  
Vol 33 (11) ◽  
pp. 1235-1242 ◽  
Author(s):  
Jun J. Yang ◽  
Wendy Landier ◽  
Wenjian Yang ◽  
Chengcheng Liu ◽  
Lindsey Hageman ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Race And Ethnicity ◽  
Genome Wide Association Study ◽  
Lymphoblastic Leukemia ◽  
Dose Intensity ◽  
Average Dose ◽  
Childhood All ◽  
Curative Therapy ◽  
Genome Wide ◽  
A Genome

Purpose Mercaptopurine (MP) is the mainstay of curative therapy for acute lymphoblastic leukemia (ALL). We performed a genome-wide association study (GWAS) to identify comprehensively the genetic basis of MP intolerance in children with ALL. Patients and Methods The discovery GWAS and replication cohorts included 657 and 371 children from two prospective clinical trials. MP dose intensity was a marker for drug tolerance and toxicities and was defined as prescribed dose divided by the planned protocol dose during maintenance therapy; its association with genotype was evaluated using a linear mixed-effects model. Results MP dose intensity varied by race and ethnicity and was negatively correlated with East Asian genetic ancestry (P < .001). The GWAS revealed two genome-wide significant loci associated with dose intensity: rs1142345 in TPMT (Tyr240Cys, present in *3A and *3C variants; P = 8.6 × 10−9) and rs116855232 in NUDT15 (P = 8.8 × 10−9), with independent replication. Patients with TT genotype at rs116855232 were exquisitely sensitive to MP, with an average dose intensity of 8.3%, compared with those with TC and CC genotypes, who tolerated 63% and 83.5% of the planned dose, respectively. The NUDT15 variant was most common in East Asians and Hispanics, rare in Europeans, and not observed in Africans, contributing to ancestry-related differences in MP tolerance. Of children homozygous for either TPMT or NUDT15 variants or heterozygous for both, 100% required ≥ 50% MP dose reduction, compared with only 7.7% of others. Conclusion We describe a germline variant in NUDT15 strongly associated with MP intolerance in childhood ALL, which may have implications for treatment individualization in this disease.

scholarly journals Genome-Wide Association Study Reveals the Genetic Basis of Chilling Tolerance in Rice at the Reproductive Stage

Plants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1722
Author(s):  
Byeong Yong Jeong ◽  
Yoonjung Lee ◽  
Yebin Kwon ◽  
Jee Hye Kim ◽  
Tae-Ho Ham ◽  
...  
Keyword(s):  
Association Study ◽  
Genetic Basis ◽  
Genome Wide Association Study ◽  
Linkage Disequilibrium Block ◽  
Chilling Tolerance ◽  
Reproductive Stage ◽  
Genome Wide Association ◽  
Matrix Analysis ◽  
Genome Wide ◽  
A Genome

A genome-wide association study (GWAS) was used to investigate the genetic basis of chilling tolerance in a collection of 117 rice accessions, including 26 Korean landraces and 29 weedy rices, at the reproductive stage. To assess chilling tolerance at the early young microspore stage, plants were treated at 12 °C for 5 days, and tolerance was evaluated using seed set fertility. GWAS, together with principal component analysis and kinship matrix analysis, revealed five quantitative trait loci (QTLs) associated with chilling tolerance on chromosomes 3, 6, and 7. The percentage of phenotypic variation explained by the QTLs was 11–19%. The genomic region underlying the QTL on chromosome 3 overlapped with a previously reported QTL associated with spikelet fertility. Subsequent bioinformatic and haplotype analyses suggested three candidate chilling-tolerance genes within the QTL linkage disequilibrium block: Os03g0305700, encoding a protein similar to peptide chain release factor 2; Os06g0495700, encoding a beta tubulin, autoregulation binding-site-domain-containing protein; and Os07g0137800, encoding a protein kinase, core-domain-containing protein. Further analysis of the detected QTLs and the candidate chilling-tolerance genes will facilitate strategies for developing chilling-tolerant rice cultivars in breeding programs.

scholarly journals Genome-Wide Association Study of H/L Traits in Chicken

Animals ◽  
2019 ◽  
Vol 9 (5) ◽  
pp. 260 ◽  
Author(s):  
Bo Zhu ◽  
Qinghe Li ◽  
Ranran Liu ◽  
Maiqing Zheng ◽  
Jie Wen ◽  
...  
Keyword(s):  
Disease Resistance ◽  
Association Study ◽  
Genetic Basis ◽  
Molecular Mechanisms ◽  
Genome Wide Association Study ◽  
Gene Annotation ◽  
Immune Defense ◽  
Genome Wide Association ◽  
Genome Wide ◽  
A Genome

Presently, the heterophil-to-lymphocyte (H/L) ratio is being studied extensively as a disease resistance trait. Through intricate mechanisms to identify and destroy pathogenic microorganisms, heterophils play a pivotal role in the immune defense systems of avian species. To reveal the genetic basis and molecular mechanisms affecting the H/L ratio, phenotypic and H/L data from 1650 white feather chicken broilers were used in performing a genome-wide association study. A self-developed, chicken-specific 55K chip was used for heterophils, lymphocytes, and H/L classification, according to individual genomic DNA profiles. We identified five significant single nucleotide polymorphisms (SNPs) when the genome-wide significance threshold was set to 5% (p < 2.42 × 10−6). A total of 15 SNPs obtained seemingly significant levels (p < 4.84 × 10−5). Gene annotation indicated that CARD11 (Caspase recruitment domain family member 11), BRIX1 (Biogenesis of ribosomes BRX1), and BANP (BTG3 associated nuclear protein) play a role in H/L-associated cell regulation and potentially constitute candidate gene regions for cellular functions dependent on H/L ratios. These results lay the foundation for revealing the genetic basis of disease resistance and future marker-assisted selection for disease resistance.

Genome-Wide Association Study Identifies a Novel Susceptibility Locus At 10p12.31-12.2 for Childhood Acute Lymphoblastic Leukemia in Ethinically Diverse Populations

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 877-877
Author(s):  
Jun J. Yang ◽  
Heng Xu ◽  
Wenjian Yang ◽  
Virginia Perez-Andreu ◽  
Meenakshi Devidas ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Racial Differences ◽  
Genetic Basis ◽  
Lymphoblastic Leukemia ◽  
Genome Wide Association ◽  
Susceptibility Locus ◽  
Diverse Populations ◽  
Childhood All ◽  
Risk Alleles ◽  
Genome Wide

Abstract Abstract 877 Genetic predisposition to childhood acute lymphoblastic leukemia (ALL) is compellingly evidenced by recent genome-wide association studies (GWAS) identifying ARID5B, IKZF1, CEBPE, and CDKN2A/B as ALL susceptibility loci. However, these 4 loci cumulatively accounted for only 8% of genetic variability in ALL risk, suggesting additional susceptibility variants yet to be identified in larger studies. Moreover, ALL GWAS has been exclusively restricted to populations of European descent, and the genetic basis of ALL susceptibility in the context of diverse ethnic background is largely unknown. This is of particular importance because the incidence of ALL varies substantially by ethnicity. Taking a multi-ethnic GWAS approach, we compared genotype frequency at 709,509 germline single nucleotide polymorphisms (SNPs) between 1,605 children with ALL and 6,661 controls of European, African, and Native American genetic ancestry (i.e., European American [EA], African American [AA], and Hispanics). After adjusting for population structures, 4 loci reached genome-wide significance threshold of P<5×10−8: 10q21.2 (ARID5B, P=5.9×10−46), 7p12.2 (IKZF1, P=5.3×10−24), 14q11.2 (CEBPE, P=9×10−12), as previously reported; and a novel ALL susceptibility locus at 10p12.31-12.2 (PIP4K2A, P=1.1×10−11). While ARID5B, IKZF1, and PIP4K2A SNPs were associated with ALL across different ethnicities, the association at the CEBPE locus was more specific to EAs. ALL risk variants at ARID5B and PIP4K2A SNPs were most common in Hispanics followed by EAs, and least common in AAs, in parallel with racial differences in the incidence of childhood ALL. We also performed multivariate analyses to determine the extent to which SNPs contribute independently to ALL susceptibility at each of the 4 loci. While associations at ARID5B and CEBPE loci were completely explained by the respective top SNP within each region, IKZF1 and PIP4K2A loci harbored multiple independent association signals. All 4 loci were validated in 3 independent replication series at P<0.05 level in multiple ethnic groups: EAs, 574 cases and 2,601 controls; AAs, 128 cases and 1,075 controls; Hispanics, 143 cases and 640 controls. For example, the top PIP4K2A SNP was significant in all 3 replication studies: EAs, P=0.0017; AAs, P=0.009; and Hispanics, P=0.041. We next examined the cumulative effects of these 4 loci on ALL susceptibility by multi-marker analyses of top SNPs at ARID5B, IKZF1, PIP4K2A, and CEBPE. In the combined discovery and replication cohorts (2,450 cases and 10,977 controls), the number of risk alleles at these 4 SNPs (genetic risk burden) was positively correlated with relative ALL risk, e.g., subjects with 6–8 copies of risk alleles (252 cases and 314 controls) were at 9.0-fold (95% confidence interval, 6.9–11.8) higher risk of developing ALL than those with 0–1 copy of the risk alleles (153 cases and 1,753 controls). Interestingly, every copy of allele C at the ARID5BSNP rs10821936 conferred a 1.93-fold increase (95% CI, 1.8–2.08) in the risk of developing ALL in children less than 10 years old (N=1,947) whereas the added disease risk by each C allele was 1.48-fold (95% CI, 1.3–1.68) in children older than 10 (N=503), implying plausible modifying effects of age on genetic predisposition to childhood ALL. The association between rs10821936 SNP genotype and age at ALL diagnosis remained significant even after adjusting for molecular subtypes. In conclusion, we reported the first multi-ethnic GWAS of childhood ALL in which we comprehensively examined the role of inherited genetic variation in ALL susceptibility in diverse populations and identified a novel susceptibility locus at 10p12.31-12.2. Our results not only shed new light on molecular etiology of childhood ALL, but also on the genetic basis of racial differences in ALL incidence. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Heritability and molecular genetic basis of antisaccade eye tracking error rate: A genome-wide association study

2014 ◽  
Vol 51 (12) ◽  
pp. 1272-1284 ◽  
Author(s):  
Uma Vaidyanathan ◽  
Stephen M. Malone ◽  
Jennifer M. Donnelly ◽  
Micah A. Hammer ◽  
Michael B. Miller ◽  
...  
Keyword(s):  
Association Study ◽  
Error Rate ◽  
Genetic Basis ◽  
Genome Wide Association Study ◽  
Molecular Genetic ◽  
Tracking Error ◽  
Genome Wide Association ◽  
Genome Wide ◽  
Molecular Genetic Basis ◽  
A Genome
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