SNP2HLA

SNP2HLA imputes amino acid polymorphisms and single nucleotide polymorphisms (SNPs) within human leukocyte antigen (HLA) genes in the major histocompatibility complex (MHC) to enable HLA variant interrogation from genome-wide association study (GWAS) datasets.

Key Features:

• Imputation strategy: Leverages long-range linkage disequilibrium between HLA loci and SNP markers across the MHC to impute classical HLA alleles and amino acid polymorphisms.
• Target loci: Supports class I loci HLA-A, -B, -C and class II loci HLA-DPA1, -DPB1, -DQA1, -DQB1, and -DRB1.
• Reference panels: Evaluated using two European-ancestry panels: HapMap-CEPH pedigrees (n=90) and the Type 1 Diabetes Genetics Consortium (T1DGC, n=5,225).
• Resolution: Imputes classical alleles at four-digit resolution and amino acid polymorphisms within HLA genes.
• Imputation accuracy: With the T1DGC panel, average allele imputation accuracy is 94.7% using the Affymetrix GeneChip 500K and 96.7% using the Illumina Immunochip; amino acid polymorphism accuracies reach 98.6% and 99.3% on these platforms, respectively.
• Reference panel importance: Demonstrates that reference panel size is more critical than SNP density of the genotyping platform for achieving high imputation accuracy.
• GWAS compatibility: Enables interrogation of HLA variation from existing GWAS datasets and was evaluated on Affymetrix GeneChip 500K and Illumina Immunochip data.
• Application in genetic studies: Facilitates association testing and fine-mapping at amino acid resolution within the MHC for disease genetics research.

Scientific Applications:

• Fine-mapping MHC signals: Enables fine-mapping of primary MHC association signals at the allele and amino acid level.
• Association testing at amino acid resolution: Supports association analyses of amino acid polymorphisms within HLA genes.
• Disease genetics: Applied to study genetic susceptibility to diseases mediated by HLA variation, including type 1 diabetes.
• Reuse of GWAS data: Allows HLA variant interrogation using existing GWAS cohorts genotyped on platforms such as Affymetrix GeneChip 500K and Illumina Immunochip.

Methodology:

Imputation uses long-range linkage disequilibrium between HLA loci and SNP markers across the MHC with reference panels (HapMap-CEPH n=90; T1DGC n=5,225) to impute classical four-digit HLA alleles and amino acid polymorphisms at class I and class II loci, with accuracy evaluated on Affymetrix GeneChip 500K and Illumina Immunochip.