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Allelic Heterogeneity

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B.k. Thelma – One of the best experts on this subject based on the ideXlab platform.

  • caucasian and asian specific rheumatoid arthritis risk loci reveal limited replication and apparent Allelic Heterogeneity in north indians
    PLOS ONE, 2012
    Co-Authors: Pushplata Prasad, Ashok Kumar, Rajiva Gupta, Ramesh C Juyal, B.k. Thelma
    Abstract:

    Genome-wide association studies and meta-analysis indicate that several genes/loci are consistently associated with rheumatoid arthritis (RA) in European and Asian populations. To evaluate the transferability status of these findings to an ethnically diverse north Indian population, we performed a replication analysis. We investigated the association of 47 single-nucleotide polymorphisms (SNPs) at 43 of these genes/loci with RA in a north Indian cohort comprising 983 RA cases and 1007 age and gender matched controls. Genotyping was done using Infinium human 660w-quad. Association analysis by chi-square test implemented in plink was carried out in two steps. Firstly, association of the index or surrogate SNP (r2>0.8, calculated from reference GIH Hap-Map population) was tested. In the second step, evidence for Allelic/locus Heterogeneity at aforementioned genes/loci was assessed for by testing additional flanking SNPs in linkage equilibrium with index/surrogate marker. Of the 44 European specific index SNPs, neither index nor surrogate SNPs were present for nine SNPs in the genotyping array. Of the remaining 35, associations were replicated at seven genes namely PTPN22 (rs1217407, p = 3×10−3); IL2–21 (rs13119723, p = 0.008); HLA-DRB1 (rs660895, p = 2.56×10−5; rs6457617, p = 1.6×10−09; rs13192471, p = 6.7×10−16); TNFA1P3 (rs9321637, p = 0.03); CCL21 (rs13293020, p = 0.01); IL2RA (rs2104286, p = 1.9×10−4) and ZEB1 (rs2793108, p = 0.006). Of the three Asian specific loci tested, rs2977227 in PADI4 showed modest association (p<0.02). Further, of the 140 SNPs (in LE with index/surrogate variant) tested, association was observed at 11 additional genes: PTPRC, AFF3, CD28, CTLA4, PXK, ANKRD55, TAGAP, CCR6, BLK, CD40 and IL2RB. This study indicates limited replication of European and Asian index SNPs and apparent Allelic Heterogeneity in RA etiology among north Indians warranting independent GWAS in this population. However, replicated associations of HLA-DRB1, PTPN22 (which confer ∼50% of the heritable risk to RA) and IL2RA suggest that cross-ethnicity fine mapping of such loci is apposite for identification of causal variants.

  • evidence of Allelic Heterogeneity for associations between the nod2 card15 gene and ulcerative colitis among north indians
    Alimentary Pharmacology & Therapeutics, 2007
    Co-Authors: Garima Juyal, Devendra Amre, Vandana Midha, Ajit Sood, Ernest G. Seidman, B.k. Thelma
    Abstract:

    Summary Background  Three common disease susceptibility variants in the NOD2 gene are associated with inflammatory bowel disease in Caucasians, but not in Asians. Aim  To screen for NOD2 variants and examine susceptibility for inflammatory bowel disease in North Indians. Methods  A case–control study was carried out in Punjab, India. Confirmed cases of ulcerative colitis and Crohn’s disease and healthy controls matched for age (±10 years) and ethnicity were studied. Besides genotyping the three disease susceptibility variants (SNP8, SNP12 and SNP13), all 12 exons were resequenced to determine other potential single nucleotide polymorphisms. Results  Two hundred and ninety-eight ulcerative colitis, 25 Crohn’s disease and 262 controls were investigated. Median age (range) at diagnosis was 39 (7–78) years for ulcerative colitis and 40 (32–58) years for Crohn’s disease. All three disease susceptibility variants were either monomorphic or rare in the population. Sequencing (n = 30) revealed two single nucleotide polymorphisms: SNP5 (268 Pro/Ser) and rs2067085 (178 Ser/Ser). The frequency of SNP5 was higher among ulcerative colitis (17% vs. 12% in controls, P = 0.016) and Crohn’s disease cases (20% vs. 12%, P = 0.28). SNP5 carriers had elevated risks for ulcerative colitis (OR = 1.72, 95% CI = 1.17–2.52, P = 0.005). Conclusions  The absence of known inflammatory bowel disease susceptibility variants and potential associations between SNP5 and ulcerative colitis in North Indians suggests the presence of Allelic Heterogeneity for ulcerative colitis susceptibility.

  • Evidence of Allelic Heterogeneity for associations between the NOD2/CARD15 gene and ulcerative colitis among North Indians
    Alimentary pharmacology & therapeutics, 2007
    Co-Authors: Garima Juyal, Devendra Amre, Vandana Midha, Ajit Sood, Ernest G. Seidman, B.k. Thelma
    Abstract:

    Summary Background  Three common disease susceptibility variants in the NOD2 gene are associated with inflammatory bowel disease in Caucasians, but not in Asians. Aim  To screen for NOD2 variants and examine susceptibility for inflammatory bowel disease in North Indians. Methods  A case–control study was carried out in Punjab, India. Confirmed cases of ulcerative colitis and Crohn’s disease and healthy controls matched for age (±10 years) and ethnicity were studied. Besides genotyping the three disease susceptibility variants (SNP8, SNP12 and SNP13), all 12 exons were resequenced to determine other potential single nucleotide polymorphisms. Results  Two hundred and ninety-eight ulcerative colitis, 25 Crohn’s disease and 262 controls were investigated. Median age (range) at diagnosis was 39 (7–78) years for ulcerative colitis and 40 (32–58) years for Crohn’s disease. All three disease susceptibility variants were either monomorphic or rare in the population. Sequencing (n = 30) revealed two single nucleotide polymorphisms: SNP5 (268 Pro/Ser) and rs2067085 (178 Ser/Ser). The frequency of SNP5 was higher among ulcerative colitis (17% vs. 12% in controls, P = 0.016) and Crohn’s disease cases (20% vs. 12%, P = 0.28). SNP5 carriers had elevated risks for ulcerative colitis (OR = 1.72, 95% CI = 1.17–2.52, P = 0.005). Conclusions  The absence of known inflammatory bowel disease susceptibility variants and potential associations between SNP5 and ulcerative colitis in North Indians suggests the presence of Allelic Heterogeneity for ulcerative colitis susceptibility.

Nathan E. Wineinger – One of the best experts on this subject based on the ideXlab platform.

  • Identification of Allelic Heterogeneity at type-2 diabetes loci and impact on prediction.
    PloS one, 2014
    Co-Authors: Yann C. Klimentidis, Jin Zhou, Nathan E. Wineinger
    Abstract:

    Although over 60 single nucleotide polymorphisms (SNPs) have been identified by meta-analysis of genome-wide association studies for type-2 diabetes (T2D) among individuals of European descent, much of the genetic variation remains unexplained. There are likely many more SNPs that contribute to variation in T2D risk, some of which may lie in the regions surrounding established SNPs – a phenomenon often referred to as Allelic Heterogeneity. Here, we use the summary statistics from the DIAGRAM consortium meta-analysis of T2D genome-wide association studies along with linkage disedisequilibrium patterns inferred from a large reference sample to identify novel SNPs associated with T2D surrounding each of the previously established risk loci. We then examine the extent to which the use of these additional SNPs improves prediction of T2D risk in an independent validation dataset. Our results suggest that multiple SNPs at each of 3 loci contribute to T2D susceptibility (TCF7L2, CDKN2A/B, and KCNQ1; p

  • identification of Allelic Heterogeneity at type 2 diabetes loci and impact on prediction
    PLOS ONE, 2014
    Co-Authors: Yann C. Klimentidis, Jin Zhou, Nathan E. Wineinger
    Abstract:

    Although over 60 single nucleotide polymorphisms (SNPs) have been identified by meta-analysis of genome-wide association studies for type-2 diabetes (T2D) among individuals of European descent, much of the genetic variation remains unexplained. There are likely many more SNPs that contribute to variation in T2D risk, some of which may lie in the regions surrounding established SNPs – a phenomenon often referred to as Allelic Heterogeneity. Here, we use the summary statistics from the DIAGRAM consortium meta-analysis of T2D genome-wide association studies along with linkage disedisequilibrium patterns inferred from a large reference sample to identify novel SNPs associated with T2D surrounding each of the previously established risk loci. We then examine the extent to which the use of these additional SNPs improves prediction of T2D risk in an independent validation dataset. Our results suggest that multiple SNPs at each of 3 loci contribute to T2D susceptibility (TCF7L2, CDKN2A/B, and KCNQ1; p<5×10−8). Using a less stringent threshold (p<5×10−4), we identify 34 additional loci with multiple associated SNPs. The addition of these SNPs slightly improves T2D prediction compared to the use of only the respective lead SNPs, when assessed using an independent validation cohort. Our findings suggest that some currently established T2D risk loci likely harbor multiple polymorphisms which contribute independently and collectively to T2D risk. This opens a promising avenue for improving prediction of T2D, and for a better understanding of the genetic architecture of T2D.

Tatiana Polushina – One of the best experts on this subject based on the ideXlab platform.

  • Allelic Heterogeneity ACROSS PSYCHOTIC DISORDERS AND RELATED PHENOTYPES
    European Neuropsychopharmacology, 2019
    Co-Authors: Tatiana Polushina, Vidar M. Steen, Ole A. Andreassen, Stephanie Le Hellard
    Abstract:

    Background Major mental illnesses have been shown to overlap at the clinical and genetic levels. The genetic overlaps have been so far explored at the single genetic variants level, but very few studies have explored how independent variants within a locus could contribute to the genetic overlaps. In our study, we intend to increase the information captured from GWASs by focusing on Allelic Heterogeneity, i.e. the contribution of several independent markers within one genetic locus, within a trait and across related traits. Methods Using summary statistics from GWASs of traits related to mental illnesses: psychotic disorders, cognitive traits and brain volumes, we first selected independent genomic regions associated in each traits after conditional regression (Yang et al. [1] ). All the genetic variants in LD with the associated signal were included in the genomic regions. We then first explored the overlaps in the regions within traits and across traits. We also scored each genomic region in each of the traits, using the Brown score for each bin, and explored the overlap in the significant regions. Results We observed Allelic Heterogeneity within and across traits. 147 genomic regions were associated with independent markers (not in LD) across several traits. We have established a map of genetic overlaps for these clusters across psychiatric disorders and relevant phenotypes (brain volumes, cognitive and personality traits). The strongest overlaps were observed in pairs: schizophreniaeducational attainment and schizophreniabipolar disorder. We have established a pipeline for identification of Allelic Heterogeneity across different phenotypes. Several of the GWAS included were too limited in power to provide significant hits yet, and will need bigger samples to yield more significant results. Discussion We identify Allelic Heterogeneity across traits, demonstrating that some genetic regions harbor independent associations with related phenotypes. Our approach is complementary to studies that explore genetic overlap at the single marker level. This improves our understanding of the impact of genetic factors in main psychotic disorders and related phenotypes, and could help to direct functional studies later.

  • analysis of the joint effect of snps to identify independent loci and Allelic Heterogeneity in schizophrenia gwas data
    Translational Psychiatry, 2017
    Co-Authors: Tatiana Polushina, Sudheer Giddaluru, Francesco Bettella, Thomas Espeseth, Astri J Lundervold, Srdjan Djurovic
    Abstract:

    We have tested published methods for capturing Allelic Heterogeneity and identifying loci of joint effects to uncover more of the “hidden heritability” of schizophrenia (SCZ). We used two tools, cojo-GCTA and multi-SNP, to analyze meta-statistics from the latest genome-wide association study (GWAS) on SCZ by the Psychiatric Genomics Consortium (PGC). Stepwise regression on markers with p values <10−7 in cojo-GCTA identified 96 independent signals. Eighty-five passed the genome-wide significance threshold. Cross-validation of cojo-GCTA by CLUMP was 76%, i.e., 26 of the loci identified by the PGC using CLUMP were found to be dependent on another locus by cojo-GCTA. The overlap between cojo-GCTA and multi-SNP was better (up to 92%). Three markers reached genome-wide significance (5 × 10−8) in a joint effect model. In addition, two loci showed possible Allelic Heterogeneity within 1-Mb genomic regions, while CLUMP analysis had identified 16 such regions. Cojo-GCTA identified fewer independent loci than CLUMP and seems to be more conservative, probably because it accounts for long-range LD and interaction effects between markers. These findings also explain why fewer loci with possible Allelic Heterogeneity remained significant after cojo-GCTA analysis. With multi-SNP, 86 markers were selected at the threshold 10−7. Multi-SNP identifies fewer independent signals, due to splitting of the data and use of smaller samples. We recommend that cojo-GCTA and multi-SNP are used for post-GWAS analysis of all traits to call independent loci. We conclude that only a few loci in SCZ show joint effects or Allelic Heterogeneity, but this could be due to lack of power for that data set.

  • Analysis of the joint effect of SNPs to identify independent loci and Allelic Heterogeneity in schizophrenia GWAS data.
    Translational psychiatry, 2017
    Co-Authors: Tatiana Polushina, Srdjan Djurovic, Sudheer Giddaluru, Francesco Bettella, Thomas Espeseth, Astri J Lundervold, Sven Cichon, Per Hoffmann, Markus M. Nöthen, Vidar M. Steen
    Abstract:

    We have tested published methods for capturing Allelic Heterogeneity and identifying loci of joint effects to uncover more of the “hidden heritability” of schizophrenia (SCZ). We used two tools, cojo-GCTA and multi-SNP, to analyze meta-statistics from the latest genome-wide association study (GWAS) on SCZ by the Psychiatric Genomics Consortium (PGC). Stepwise regression on markers with p values

Jeffrey A Whitsett – One of the best experts on this subject based on the ideXlab platform.

  • Allelic Heterogeneity in hereditary surfactant protein b sp b deficiency
    American Journal of Respiratory and Critical Care Medicine, 2000
    Co-Authors: Lawrence M Nogee, Susan E Wert, Sherri A Proffit, William M. Hull, Jeffrey A Whitsett
    Abstract:

    Inability to produce surfactant protein B (SP-B) causes fatal neonatal respiratory disease. A frame-shift mutation (121ins2) is the predominant but not exclusive cause of disease. To determine the range of mechanisms responsible for SP-B deficiency, both alleles from 32 affected infants were characterized. Sixteen infants were homozygous for the 121ins2 mutation, 10 infants were heterozygous for the 121ins2 and another mutation, and six infants were homozygous for other mutations. Thirteen novel SP-B gene mutations were identified, which were not found in a control population. One novel mutation was found in two unrelated families. Surfactant protein expression was evaluated by immunohistochemistry and/or protein blotting. Absence of proSP-B and mature SP-B was associated with nonsense and frame-shift mutations. In contrast, proSP-B expresssion was associated with missense mutations, or mutations causing in-frame deletions or insertions, and low levels of mature SP-B expression were associated with four m…

  • Allelic Heterogeneity in hereditary surfactant protein b sp b deficiency
    American Journal of Respiratory and Critical Care Medicine, 2000
    Co-Authors: Lawrence M Nogee, Susan E Wert, Sherri A Proffit, William M. Hull, Jeffrey A Whitsett
    Abstract:

    Inability to produce surfactant protein B (SP-B) causes fatal neonatal respiratory disease. A frame-shift mutation (121ins2) is the predominant but not exclusive cause of disease. To determine the range of mechanisms responsible for SP-B deficiency, both alleles from 32 affected infants were characterized. Sixteen infants were homozygous for the 121ins2 mutation, 10 infants were heterozygous for the 121ins2 and another mutation, and six infants were homozygous for other mutations. Thirteen novel SP-B gene mutations were identified, which were not found in a control population. One novel mutation was found in two unrelated families. Surfactant protein expression was evaluated by immunohistochemistry and/or protein blotting. Absence of proSP-B and mature SP-B was associated with nonsense and frame-shift mutations. In contrast, proSP-B expression was associated with missense mutations, or mutations causing in-frame deletions or insertions, and low levels of mature SP-B expression were associated with four mutations. Extracellular staining for proSP-C and/or aberrantly processed SP-C was observed in lungs of all infants with SP-B gene mutations. Hereditary SP-B deficiency is caused by a variety of distinct mutations in the SP-B gene and may be associated with reduced, as well as absent, levels of mature SP-B, likely caused by impaired processing of proSP-B.

Yann C. Klimentidis – One of the best experts on this subject based on the ideXlab platform.

  • Identification of Allelic Heterogeneity at type-2 diabetes loci and impact on prediction.
    PloS one, 2014
    Co-Authors: Yann C. Klimentidis, Jin Zhou, Nathan E. Wineinger
    Abstract:

    Although over 60 single nucleotide polymorphisms (SNPs) have been identified by meta-analysis of genome-wide association studies for type-2 diabetes (T2D) among individuals of European descent, much of the genetic variation remains unexplained. There are likely many more SNPs that contribute to variation in T2D risk, some of which may lie in the regions surrounding established SNPs – a phenomenon often referred to as Allelic Heterogeneity. Here, we use the summary statistics from the DIAGRAM consortium meta-analysis of T2D genome-wide association studies along with linkage disequilibrium patterns inferred from a large reference sample to identify novel SNPs associated with T2D surrounding each of the previously established risk loci. We then examine the extent to which the use of these additional SNPs improves prediction of T2D risk in an independent validation dataset. Our results suggest that multiple SNPs at each of 3 loci contribute to T2D susceptibility (TCF7L2, CDKN2A/B, and KCNQ1; p

  • identification of Allelic Heterogeneity at type 2 diabetes loci and impact on prediction
    PLOS ONE, 2014
    Co-Authors: Yann C. Klimentidis, Jin Zhou, Nathan E. Wineinger
    Abstract:

    Although over 60 single nucleotide polymorphisms (SNPs) have been identified by meta-analysis of genome-wide association studies for type-2 diabetes (T2D) among individuals of European descent, much of the genetic variation remains unexplained. There are likely many more SNPs that contribute to variation in T2D risk, some of which may lie in the regions surrounding established SNPs – a phenomenon often referred to as Allelic Heterogeneity. Here, we use the summary statistics from the DIAGRAM consortium meta-analysis of T2D genome-wide association studies along with linkage disequilibrium patterns inferred from a large reference sample to identify novel SNPs associated with T2D surrounding each of the previously established risk loci. We then examine the extent to which the use of these additional SNPs improves prediction of T2D risk in an independent validation dataset. Our results suggest that multiple SNPs at each of 3 loci contribute to T2D susceptibility (TCF7L2, CDKN2A/B, and KCNQ1; p<5×10−8). Using a less stringent threshold (p<5×10−4), we identify 34 additional loci with multiple associated SNPs. The addition of these SNPs slightly improves T2D prediction compared to the use of only the respective lead SNPs, when assessed using an independent validation cohort. Our findings suggest that some currently established T2D risk loci likely harbor multiple polymorphisms which contribute independently and collectively to T2D risk. This opens a promising avenue for improving prediction of T2D, and for a better understanding of the genetic architecture of T2D.