scholarly journals Genome-Wide Association Study of Cause-Specific Transplant-Related Mortality (TRM) after HLA-Matched Unrelated Donor Allogeneic BMT for Acute Leukemia or Myelodysplastic Syndrome Demonstrates Unique, Non-Overlapping Genetic Associations (Discovery-BMT)

2016 ◽  
Vol 22 (3) ◽  
pp. S74-S75
Author(s):  
Theresa E. Hahn ◽  
Leah Preus ◽  
Philip L. McCarthy ◽  
Marcelo C. Pasquini ◽  
Kenan Onel ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Myelodysplastic Syndrome ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Unrelated Donor ◽  
Genetic Associations ◽  
Matched Unrelated Donor ◽  
Genome Wide ◽  
Related Mortality

Genetic associations with taxane-induced neuropathy by a genome-wide association study (GWAS) in E5103.

2011 ◽  
Vol 29 (15_suppl) ◽  
pp. 1000-1000 ◽  
Author(s):  
B. P. Schneider ◽  
L. Li ◽  
K. Miller ◽  
D. Flockhart ◽  
M. Radovich ◽  
...  
Keyword(s):  
Association Study ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Genetic Associations ◽  
Genome Wide ◽  
A Genome

Genome-Wide Association Study of Overall and Progression-Free Survival after HLA-Matched Unrelated Donor Blood and Marrow Transplantation (DISCOVeRY-BMT study)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 397-397
Author(s):  
Theresa Hahn ◽  
Leah Preus ◽  
Philip L. McCarthy ◽  
Marcelo C. Pasquini ◽  
Kenan Onel ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Survival Outcomes ◽  
Unrelated Donor ◽  
Matched Unrelated Donor ◽  
Advisory Committees ◽  
Genome Wide ◽  
One Year

Abstract While survival outcomes after HLA-matched unrelated donor (URD) blood and marrow transplant (BMT) have significantly improved over the last 2 decades, about 40% of patients die of various causes before one-year post-URD BMT. We performed a genome-wide association study (GWAS) named DISCOVeRY-BMT (Determining the Influence of Susceptibility COnveying Variants Related to one-Year mortality after BMT) of overall (OS) and progression-free (PFS) survival in 3,532 patients treated for AML, ALL or MDS and reported to CIBMTR from 2000-2011 and their 8/8 HLA-matched URDs. Cohort 1 consisted of 2,609 patients with 10/10 HLA-matched URD BMT from 2000-08; Cohort 2 consisted of 923 patients with 10/10 HLA-matched URD BMT from 2009-11 and 8/8 (but <10/10) HLA-matched URD BMT from 2000-11. Genotyping on recipients and donors was performed using the HumanOmniExpress-24 BeadChip (Illumina, San Diego, CA), containing approximately 730,000 single nucleotide polymorphisms (SNPs); the CEU reference panel from the 1000 Genomes project (March 2012 release) was used to impute additional genotypes not available on the GWAS chip or that failed typing. Samples were pre-phased with SHAPEIT and genotypes inferred using IMPUTE2. After quality control, Cohort 1 included 2,108 recipients and 2,052 donors and Cohort 2 included 773 recipients and 760 donors of European-American ancestry typed at 637,655 markers and ~9 million imputed SNPs. Each SNP was measured for association with OS and PFS using Cox proportional hazard models in R. All models included age at BMT, diagnosis (AML, ALL, MDS), disease status at BMT (early, intermediate, advanced), cell source (blood, marrow) and year of BMT. P-values were combined using METAL software with weights proportional to the square root of the number of cases. We report results for a combined P -value (Pmeta) <5x10-8. The T allele of rs9990017 in recipients is significantly associated with better OS (Table) yielding about a 30% decreased hazard of all causes of death including disease relapse, graft-versus-host disease, infection and organ failure. Analysis of the effect of donor genotype at this SNP shows no evidence of association with OS or PFS. The strongest imputed association in this region (info score >.98) was rs9857765 with the T allele at this locus conferring a significantly improved OS in both cohorts (Table). Two SNPs (rs9845520 and rs9839074) in strong linkage disequilibrium (r2 =.94) with both rs9857765 and rs9990017, are predicted to affect transcription factor binding (Regulomedb score=2b) of the highly-conserved gene MBNL1 and the common allele in rs9839074 is predicted to be in an important position in the GATA1 (erythroid development) motif and a binding site for CEBPB, STAT3 and FOS across multiple cell lines. MBNL1 protein is expressed in most blood and marrow hematopoietic cells, while MBNL1 mRNA is expressed in many organs. CEBPB regulates immune response genes, is required for normal macrophage function/differentiation and can interact with (among others) glucocorticoid receptor, IL-6, TNF-alpha and transporter proteins conferring multi-drug resistance (ABCC2, ABCB1). Normal activation of STAT3 is required for self-renewal of embryonic stem cells and differentiation of TH17 cells, while constitutive activation of STAT3 is associated with poor prognosis in acute leukemia. FOS is involved with CD16+ signaling in NK cells, vitamin D receptor gene regulation in osteoporosis, and proliferation of hematopoietic cells, among other roles. A region on 13q34 showed evidence of association with PFS; recipients whose donor had a T allele at rs11617176 showed improved PFS compared to those whose donors had the C allele (see Table). This region contains variants identified in other GWAS of mean platelet volume, coronary artery disease, interstitial lung disease, response to tocilizumab in rheumatoid arthritis patients and renal transplant outcomes, among others. Our study, DISCOVeRY-BMT, is the first GWAS for URD BMT survival outcomes. Confirmation of these findings in a third cohort, genotyping of imputed SNPs, and further studies of the functional consequences of these SNPs may provide more individualized risk prediction and prognosis, while confirmation of rs11617176 may aid in donor selection. Table 1. Table 1. Disclosures Hahn: Novartis: Equity Ownership; NIH/NHLBI: Research Funding. McCarthy:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; The Binding Site: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sucheston-Campbell:NIH/NHLBI: Research Funding.

A family-based genome-wide association study reveals an association of spondyloarthritis with MAPK14

2016 ◽  
Vol 76 (1) ◽  
pp. 310-314 ◽  
Author(s):  
Félicie Costantino ◽  
Alice Talpin ◽  
Roula Said-Nahal ◽  
Ariane Leboime ◽  
Elena Zinovieva ◽  
...  
Keyword(s):  
Association Study ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
P Value ◽  
Nucleotide Polymorphisms ◽  
Genetic Associations ◽  
Gwas Study ◽  
Genome Wide ◽  
Multiplex Families ◽  
Family Based

ObjectiveMore than 40 loci have been associated with ankylosing spondylitis (AS), but less is known about genetic associations in spondyloarthritis (SpA) as a whole. We conducted a family-based genome-wide association study (GWAS) to identify new non-major histocompatibility complex (MHC) genetic factors associated with SpA.Methods906 subjects from 156 French multiplex families, including 438 with SpA, were genotyped using Affymetrix 250K microarrays. Association was tested with Unphased. The best-associated non-MHC single nucleotide polymorphisms (SNPs) were then genotyped in two independent familial cohorts (including 215 French and 294 North American patients with SpA, respectively) to replicate associations.Results43 non-MHC SNPs yielded an association signal with SpA in the discovery cohort (p<1×10−4). In the extension studies, association was replicated at a nominal p value of p<0.05 for 16 SNPs in the second cohort and for three SNPs in the third cohort. Combined analysis identified an association close to genome-wide significance between rs7761118, an intronic SNP of MAPK14, and SpA (p=3.5×10−7). Such association appeared to be independent of HLA-B27.ConclusionsWe report here for the first time a family-based GWAS study on SpA and identified an associated polymorphism near MAPK14. Further analyses are needed to better understand the functional basis of this genetic association.

scholarly journals Genetics of fasting and postprandial metabolite levels are overlapping

2018 ◽  
Vol 50 (4) ◽  
pp. 235-236
Author(s):  
Ruifang Li-Gao ◽  
Renée de Mutsert ◽  
Frits R. Rosendaal ◽  
Ko Willems van Dijk ◽  
Dennis O. Mook-Kanamori
Keyword(s):  
Association Study ◽  
Human Body ◽  
Genetic Basis ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Genetic Associations ◽  
Mixed Meal ◽  
Genome Wide ◽  
A Genome ◽  
Metabolite Concentrations

In 2015, a genome-wide association study described 59 independent signals that showed strong associations with 85 fasting metabolite concentrations as measured by the Biocrates AbsoluteIDQ p150 kit. However, the human body resides in a nonfasting state for the greater part of the day, and the genetic basis of postprandial metabolite concentrations remains largely unknown. We systematically examined these previously identified genetic associations in postprandial metabolite concentrations after a mixed meal. Of these 85 metabolites, 23 were identified with significant changes after the meal, for which 38 gene-metabolite associations were analyzed. Of these 38 associations, 31 gene-metabolite associations were replicated with postprandial metabolite concentrations. These data indicate that the genetics of fasting and postprandial metabolite levels are significantly overlapping.

scholarly journals A Multinational Arab Genome‐Wide Association Study Identifies New Genetic Associations for Rheumatoid Arthritis

2017 ◽  
Vol 69 (5) ◽  
pp. 976-985 ◽  
Author(s):  
Richa Saxena ◽  
Robert M. Plenge ◽  
Andrew C. Bjonnes ◽  
Hassan S. Dashti ◽  
Yukinori Okada ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Genetic Associations ◽  
Genome Wide

scholarly journals Interaction between GALNT12 and C1GALT1 Associates with Galactose-Deficient IgA1 and IgA Nephropathy

2021 ◽  
Vol 32 (3) ◽  
pp. 545-552
Author(s):  
Yan-Na Wang ◽  
Xu-Jie Zhou ◽  
Pei Chen ◽  
Gui-Zhen Yu ◽  
Xue Zhang ◽  
...  
Keyword(s):  
Association Study ◽  
Iga Nephropathy ◽  
Genome Wide Association Study ◽  
Disease Risk ◽  
Serum Levels ◽  
Genetic Interactions ◽  
Genome Wide Association ◽  
Healthy Controls ◽  
Genetic Associations ◽  
Genome Wide

BackgroundGalactose-deficient IgA1 plays a key role in the pathogenesis of IgA nephropathy, the most common primary GN worldwide. Although serum levels of galactose-deficient IgA1 have a strong genetic component, the genetic link between this molecule and IgA nephropathy has not yet been clearly established.MethodsTo identify novel loci associated with galactose-deficient IgA1, we performed a quantitative genome-wide association study for serum galactose-deficient IgA1 levels, on the basis of two different genome-wide association study panels conducted in 1127 patients with IgA nephropathy. To test genetic associations with susceptibility to IgA nephropathy, we also enrolled 2352 patients with biopsy-diagnosed IgA nephropathy and 2632 healthy controls. Peripheral blood samples from 59 patients and 27 healthy controls were also collected for gene expression analysis.ResultsWe discovered two loci, in C1GALT1 and GALNT12, that achieved genome-wide significance, explaining about 3.7% and 3.4% of variance in serum galactose-deficient IgA1 levels, respectively. We confirmed the previously reported association of C1GALT1 with serum galactose-deficient IgA1 levels, but with a different lead single-nucleotide polymorphism (rs10238682; β=0.26, P=1.20×10−9); the locus we identified at GALNT12 (rs7856182; β=0.73, P=2.38×10−9) was novel. Of more interest, we found that GALNT12 exhibits genetic interactions with C1GALT1 in both galactose-deficient IgA1 levels (P=1.40×10−2) and disease risk (P=6.55×10−3). GALNT12 mRNA expression in patients with IgA nephropathy was significantly lower compared with healthy controls.ConclusionsOur data identify GALNT12 as a novel gene associated with galactose-deficient IgA1 and suggest novel genetic interactions. These findings support a key role of genetically conferred dysregulation of galactose-deficient IgA1 in the development of IgA nephropathy.

scholarly journals A genome-wide association study finds novel genetic associations with broadly-defined headache in UK Biobank (N = 223,773)

2017 ◽  
Author(s):  
Weihua Meng ◽  
Mark J Adams ◽  
Harry L Hebert ◽  
Ian J Deary ◽  
Andrew M McIntosh ◽  
...  
Keyword(s):  
Association Study ◽  
Genome Wide Association Study ◽  
Genetic Correlations ◽  
Genome Wide Association ◽  
Uk Biobank ◽  
Genetic Associations ◽  
Psychological Traits ◽  
Genome Wide ◽  
A Genome ◽  
The Uk

AbstractHeadache is the most common neurological symptom and a leading cause of years lived with disability. We sought to identify the genetic variants associated with a broadly-defined headache phenotype in 223,773 subjects from the UK Biobank cohort. We defined headache based on a specific question answered by the UK Biobank participants. We performed a genome-wide association study of headache as a single entity, using 74,461 cases and 149,312 controls. We identified 3,343 SNPs which reached the genome-wide significance level of P < 5 × 10−8. The SNPs were located in 28 loci, with the top SNP of rs11172113 in the LRP1 gene having a P value of 4.92 × 10−47. Of the 28 loci, 14 have previously been associated with migraine. Among 14 new loci, rs77804065 with a P value of 5.87 × 10−15 in the LINC02210-CRHR1 gene was the top SNP.Positive relationships (P < 0.001) between multiple brain tissues and genetic associations were identified through tissue expression analysis, whereas no vascular related tissues showed significant relationships. We identified several significant positive genetic correlations between headache and other psychological traits including neuroticism, depressive symptoms, insomnia, and major depressive disorder.Our results suggest that brain function is closely related to broadly-defined headache. In addition, we also found that many psychological traits have genetic correlations with headache.

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