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Construction and application of a Korean reference panel for imputing classical alleles and amino acids of human leukocyte antigen genes.

Kim K, Bang SY, Lee HS, Bae SC - PLoS ONE (2014)

Bottom Line: Average concordance rates were 95.6% and 91.1% at 2-digit and 4-digit allele resolutions, respectively.The imputation accuracy was minimally affected by SNP density of a test dataset for imputation.In conclusion, the Korean HLA reference panel we developed was highly suitable for imputing HLA alleles and amino acids from MHC SNPs in East Asians, including Koreans.

View Article: PubMed Central - PubMed

Affiliation: Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Republic of Korea; Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America.

ABSTRACT
Genetic variations of human leukocyte antigen (HLA) genes within the major histocompatibility complex (MHC) locus are strongly associated with disease susceptibility and prognosis for many diseases, including many autoimmune diseases. In this study, we developed a Korean HLA reference panel for imputing classical alleles and amino acid residues of several HLA genes. An HLA reference panel has potential for use in identifying and fine-mapping disease associations with the MHC locus in East Asian populations, including Koreans. A total of 413 unrelated Korean subjects were analyzed for single nucleotide polymorphisms (SNPs) at the MHC locus and six HLA genes, including HLA-A, -B, -C, -DRB1, -DPB1, and -DQB1. The HLA reference panel was constructed by phasing the 5,858 MHC SNPs, 233 classical HLA alleles, and 1,387 amino acid residue markers from 1,025 amino acid positions as binary variables. The imputation accuracy of the HLA reference panel was assessed by measuring concordance rates between imputed and genotyped alleles of the HLA genes from a subset of the study subjects and East Asian HapMap individuals. Average concordance rates were 95.6% and 91.1% at 2-digit and 4-digit allele resolutions, respectively. The imputation accuracy was minimally affected by SNP density of a test dataset for imputation. In conclusion, the Korean HLA reference panel we developed was highly suitable for imputing HLA alleles and amino acids from MHC SNPs in East Asians, including Koreans.

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Related in: MedlinePlus

Frequencies and disease effect sizes of imputed and genotyped HLA-DRB1 alleles.We revisited our previous rheumatoid arthritis association studies using either typed SNPs [16] or HLA alleles [17]. After imputing HLA variants from the SNP-based dataset, (A) frequencies and (B) disease effect sizes of the imputed classical alleles of HLA-DRB1 were compared with those of genotyped classical alleles in the HLA-based dataset.
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pone-0112546-g002: Frequencies and disease effect sizes of imputed and genotyped HLA-DRB1 alleles.We revisited our previous rheumatoid arthritis association studies using either typed SNPs [16] or HLA alleles [17]. After imputing HLA variants from the SNP-based dataset, (A) frequencies and (B) disease effect sizes of the imputed classical alleles of HLA-DRB1 were compared with those of genotyped classical alleles in the HLA-based dataset.

Mentions: We found highly correlated allele frequencies between imputed and genotyped HLA-DRB1 alleles (correlation coefficient r = 0.976 at 2-digit resolution and r = 0.932 at 4-digit resolution; Figure 2A), although a large portion of subjects was not examined in the both studies. The effect sizes of each HLA allele were also highly concordant between the two datasets (r = 0.984 at 2-digit resolution and r = 0.938 at 4-digit resolution; Figure 2B), which demonstrating reliability, validity and usefulness of the Korean reference panel in MHC-disease association studies.


Construction and application of a Korean reference panel for imputing classical alleles and amino acids of human leukocyte antigen genes.

Kim K, Bang SY, Lee HS, Bae SC - PLoS ONE (2014)

Frequencies and disease effect sizes of imputed and genotyped HLA-DRB1 alleles.We revisited our previous rheumatoid arthritis association studies using either typed SNPs [16] or HLA alleles [17]. After imputing HLA variants from the SNP-based dataset, (A) frequencies and (B) disease effect sizes of the imputed classical alleles of HLA-DRB1 were compared with those of genotyped classical alleles in the HLA-based dataset.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4232350&req=5

pone-0112546-g002: Frequencies and disease effect sizes of imputed and genotyped HLA-DRB1 alleles.We revisited our previous rheumatoid arthritis association studies using either typed SNPs [16] or HLA alleles [17]. After imputing HLA variants from the SNP-based dataset, (A) frequencies and (B) disease effect sizes of the imputed classical alleles of HLA-DRB1 were compared with those of genotyped classical alleles in the HLA-based dataset.
Mentions: We found highly correlated allele frequencies between imputed and genotyped HLA-DRB1 alleles (correlation coefficient r = 0.976 at 2-digit resolution and r = 0.932 at 4-digit resolution; Figure 2A), although a large portion of subjects was not examined in the both studies. The effect sizes of each HLA allele were also highly concordant between the two datasets (r = 0.984 at 2-digit resolution and r = 0.938 at 4-digit resolution; Figure 2B), which demonstrating reliability, validity and usefulness of the Korean reference panel in MHC-disease association studies.

Bottom Line: Average concordance rates were 95.6% and 91.1% at 2-digit and 4-digit allele resolutions, respectively.The imputation accuracy was minimally affected by SNP density of a test dataset for imputation.In conclusion, the Korean HLA reference panel we developed was highly suitable for imputing HLA alleles and amino acids from MHC SNPs in East Asians, including Koreans.

View Article: PubMed Central - PubMed

Affiliation: Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Republic of Korea; Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America.

ABSTRACT
Genetic variations of human leukocyte antigen (HLA) genes within the major histocompatibility complex (MHC) locus are strongly associated with disease susceptibility and prognosis for many diseases, including many autoimmune diseases. In this study, we developed a Korean HLA reference panel for imputing classical alleles and amino acid residues of several HLA genes. An HLA reference panel has potential for use in identifying and fine-mapping disease associations with the MHC locus in East Asian populations, including Koreans. A total of 413 unrelated Korean subjects were analyzed for single nucleotide polymorphisms (SNPs) at the MHC locus and six HLA genes, including HLA-A, -B, -C, -DRB1, -DPB1, and -DQB1. The HLA reference panel was constructed by phasing the 5,858 MHC SNPs, 233 classical HLA alleles, and 1,387 amino acid residue markers from 1,025 amino acid positions as binary variables. The imputation accuracy of the HLA reference panel was assessed by measuring concordance rates between imputed and genotyped alleles of the HLA genes from a subset of the study subjects and East Asian HapMap individuals. Average concordance rates were 95.6% and 91.1% at 2-digit and 4-digit allele resolutions, respectively. The imputation accuracy was minimally affected by SNP density of a test dataset for imputation. In conclusion, the Korean HLA reference panel we developed was highly suitable for imputing HLA alleles and amino acids from MHC SNPs in East Asians, including Koreans.

Show MeSH
Related in: MedlinePlus