PMID- 23762245
OWN - NLM
STAT- MEDLINE
DCOM- 20140114
LR  - 20221207
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 8
IP  - 6
DP  - 2013
TI  - Imputing amino acid polymorphisms in human leukocyte antigens.
PG  - e64683
LID - 10.1371/journal.pone.0064683 [doi]
LID - e64683
AB  - 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 describe a computational strategy, 
      SNP2HLA, to impute classical alleles and amino acid polymorphisms at class I 
      (HLA-A, -B, -C) and class II (-DPA1, -DPB1, -DQA1, -DQB1, and -DRB1) loci. To 
      characterize performance of SNP2HLA, we constructed two European ancestry 
      reference panels, one based on data collected in HapMap-CEPH pedigrees (90 
      individuals) and another based on data collected by the Type 1 Diabetes Genetics 
      Consortium (T1DGC, 5,225 individuals). We imputed HLA alleles in an independent 
      data set from the British 1958 Birth Cohort (N = 918) with gold standard 
      four-digit HLA types and SNPs genotyped using the Affymetrix GeneChip 500 K and 
      Illumina Immunochip microarrays. We demonstrate that the sample size of the 
      reference panel, rather than SNP density of the genotyping platform, is critical 
      to achieve high imputation accuracy. Using the larger T1DGC reference panel, the 
      average accuracy at four-digit resolution is 94.7% using the low-density 
      Affymetrix GeneChip 500 K, and 96.7% using the high-density Illumina Immunochip. 
      For amino acid polymorphisms within HLA genes, we achieve 98.6% and 99.3% 
      accuracy using the Affymetrix GeneChip 500 K and Illumina Immunochip, 
      respectively. Finally, we demonstrate how imputation and association testing at 
      amino acid resolution can facilitate fine-mapping of primary MHC association 
      signals, giving a specific example from type 1 diabetes.
FAU - Jia, Xiaoming
AU  - Jia X
AD  - Harvard-MIT (Massachusetts Institute of Technology) Division of Health Sciences 
      and Technology, Boston, Massachusetts, United States of America.
FAU - Han, Buhm
AU  - Han B
FAU - Onengut-Gumuscu, Suna
AU  - Onengut-Gumuscu S
FAU - Chen, Wei-Min
AU  - Chen WM
FAU - Concannon, Patrick J
AU  - Concannon PJ
FAU - Rich, Stephen S
AU  - Rich SS
FAU - Raychaudhuri, Soumya
AU  - Raychaudhuri S
FAU - de Bakker, Paul I W
AU  - de Bakker PI
LA  - eng
GR  - 1R01AR062886-01/AR/NIAMS NIH HHS/United States
GR  - K08AR055688/AR/NIAMS NIH HHS/United States
GR  - 068545/Z/02/WT_/Wellcome Trust/United Kingdom
GR  - G1001799/MRC_/Medical Research Council/United Kingdom
GR  - U01 DK062418/DK/NIDDK NIH HHS/United States
GR  - R01 AR062886/AR/NIAMS NIH HHS/United States
GR  - G0000934/MRC_/Medical Research Council/United Kingdom
GR  - WT_/Wellcome Trust/United Kingdom
GR  - K08 AR055688/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20130606
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Amino Acids)
RN  - 0 (HLA Antigens)
RN  - 0 (Histocompatibility Antigens Class I)
RN  - 0 (Histocompatibility Antigens Class II)
SB  - IM
MH  - Alleles
MH  - Amino Acids/*genetics/immunology
MH  - Chromosome Mapping
MH  - Diabetes Mellitus, Type 1/ethnology/*genetics/immunology
MH  - Genetic Predisposition to Disease
MH  - Genome-Wide Association Study
MH  - HLA Antigens/*genetics/immunology
MH  - HapMap Project
MH  - Haplotypes
MH  - Histocompatibility Antigens Class I/*genetics/immunology
MH  - Histocompatibility Antigens Class II/*genetics/immunology
MH  - Humans
MH  - Linkage Disequilibrium
MH  - *Polymorphism, Single Nucleotide
MH  - White People
PMC - PMC3675122
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2013/06/14 06:00
MHDA- 2014/01/15 06:00
PMCR- 2013/06/06
CRDT- 2013/06/14 06:00
PHST- 2013/02/14 00:00 [received]
PHST- 2013/04/17 00:00 [accepted]
PHST- 2013/06/14 06:00 [entrez]
PHST- 2013/06/14 06:00 [pubmed]
PHST- 2014/01/15 06:00 [medline]
PHST- 2013/06/06 00:00 [pmc-release]
AID - PONE-D-13-06894 [pii]
AID - 10.1371/journal.pone.0064683 [doi]
PST - epublish
SO  - PLoS One. 2013 Jun 6;8(6):e64683. doi: 10.1371/journal.pone.0064683. Print 2013.