2013
DOI: 10.1371/journal.pone.0064683
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Imputing Amino Acid Polymorphisms in Human Leukocyte Antigens

Abstract: DNA sequence variation within human leukocyte antigen (HLA) genes mediate susceptibility to a wide range of human diseases. The complex genetic structure of the major histocompatibility complex (MHC) makes it difficult, however, to collect genotyping data in large cohorts. Long-range linkage disequilibrium between HLA loci and SNP markers across the major histocompatibility complex (MHC) region offers an alternative approach through imputation to interrogate HLA variation in existing GWAS data sets. Here we de… Show more

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Cited by 577 publications
(733 citation statements)
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References 40 publications
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“…Second, leveraging HLA imputation using SNP2HLA, 17 this is the first large study to implicate variants in HLA-DQB1 and the DQB1*02 classical HLA allele in AMD susceptibility. Our findings here demonstrate how improved coverage of genotyping arrays and imputation to more comprehensive reference panels can lead to novel findings, even for traits that have been investigated in depth in previous genetic association studies.…”
Section: Discussionmentioning
confidence: 99%
See 2 more Smart Citations
“…Second, leveraging HLA imputation using SNP2HLA, 17 this is the first large study to implicate variants in HLA-DQB1 and the DQB1*02 classical HLA allele in AMD susceptibility. Our findings here demonstrate how improved coverage of genotyping arrays and imputation to more comprehensive reference panels can lead to novel findings, even for traits that have been investigated in depth in previous genetic association studies.…”
Section: Discussionmentioning
confidence: 99%
“…Following QC, we conducted imputation of classical HLA alleles and aminoacid polymorphisms at class I (HLA-A, -B, -C) and class II (-DPA1, -DPB1, -DQA1, -DQB1, and -DRB1) loci using SNP2HLA, which utilizes a reference panel of 5225 European descent individuals from the T1DGC reference panel that has been described in detail by Jia et al 17 In total, we examined 6937 SNPs, 1000 amino-acid changes, and 172 classical HLA alleles in the HLA region with minor allele FRQ 40.01 and imputation info metrics 40.80. Because a number of AMD risk loci have large effects on the risk of disease, we also imputed previously established AMD risk variants of large effect in CFH, ARMS2/HTRA1, CFB/SKIV2L, and C3 gene regions based on the 1000 Genomes Project 24 reference panel (March 2012 release) using IMPUTE2 v2.3.0 and standard procedures.…”
Section: Genotyping Qc Imputation and Genetic Ancestry Of The Geramentioning
confidence: 99%
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“…Significance was defined as P  < 6.8 × 10 −6 based on a Bonferroni correction of the 7,323 markers imputed by SNP2HLA 23. For consistency, the most associated variant was used in the stepwise conditional analysis.…”
Section: Methodsmentioning
confidence: 99%
“…[40][41][42] In addition, GWAS discoveries and interpretation have benefited substantially from improved algorithms in statistical imputation of unobserved genotypes and statistical imputation of human leukocyte antigen (HLA) genes and amino acid polymorphisms. [43][44][45][46] Common Variants Together Tag a Substantial Proportion of Additive Genetic Variance In addition to enabling the discovery of specific trait-locus associations, GWASs have facilitated estimation of how much of the total additive genetic variation due to segregating variants in the population is tagged by genotyped and imputed SNPs. This quantification of ''SNP heritability'' is informative with respect to the unknown genetic architecture of the trait.…”
Section: Pleiotropy Is Pervasivementioning
confidence: 99%