PMID- 35597955
OWN - NLM
STAT- MEDLINE
DCOM- 20220524
LR  - 20230308
IS  - 1755-8794 (Electronic)
IS  - 1755-8794 (Linking)
VI  - 15
IP  - 1
DP  - 2022 May 21
TI  - Exome-wide analysis of copy number variation shows association of the human 
      leukocyte antigen region with asthma in UK Biobank.
PG  - 119
LID - 10.1186/s12920-022-01268-y [doi]
LID - 119
AB  - BACKGROUND: The role of copy number variants (CNVs) in susceptibility to asthma 
      is not well understood. This is, in part, due to the difficulty of accurately 
      measuring CNVs in large enough sample sizes to detect associations. The recent 
      availability of whole-exome sequencing (WES) in large biobank studies provides an 
      unprecedented opportunity to study the role of CNVs in asthma. METHODS: We called 
      common CNVs in 49,953 individuals in the first release of UK Biobank WES using 
      ClinCNV software. CNVs were tested for association with asthma in a stage 1 
      analysis comprising 7098 asthma cases and 36,578 controls from the first release 
      of sequencing data. Nominally-associated CNVs were then meta-analysed in stage 2 
      with an additional 17,280 asthma cases and 115,562 controls from the second 
      release of UK Biobank exome sequencing, followed by validation and fine-mapping. 
      RESULTS: Five of 189 CNVs were associated with asthma in stage 2, including a 
      deletion overlapping the HLA-DQA1 and HLA-DQB1 genes, a duplication of 
      CHROMR/PRKRA, deletions within MUC22 and TAP2, and a duplication in FBRSL1. The 
      HLA-DQA1, HLA-DQB1, MUC22 and TAP2 genes all reside within the human leukocyte 
      antigen (HLA) region on chromosome 6. In silico analyses demonstrated that the 
      deletion overlapping HLA-DQA1 and HLA-DQB1 is likely to be an artefact arising 
      from under-mapping of reads from non-reference HLA haplotypes, and that the 
      CHROMR/PRKRA and FBRSL1 duplications represent presence/absence of pseudogenes 
      within the HLA region. Bayesian fine-mapping of the HLA region suggested that 
      there are two independent asthma association signals. The variants with the 
      largest posterior inclusion probability in the two credible sets were an amino 
      acid change in HLA-DQB1 (glutamine to histidine at residue 253) and a 
      multi-allelic amino acid change in HLA-DRB1 (presence/absence of serine, glycine 
      or leucine at residue 11). CONCLUSIONS: At least two independent loci 
      characterised by amino acid changes in the HLA-DQA1, HLA-DQB1 and HLA-DRB1 genes 
      are likely to account for association of SNPs and CNVs in this region with 
      asthma. The high divergence of haplotypes in the HLA can give rise to spurious 
      CNVs, providing an important, cautionary tale for future large-scale analyses of 
      sequencing data.
CI  - (c) 2022. The Author(s).
FAU - Fawcett, Katherine A
AU  - Fawcett KA
AUID- ORCID: 0000-0002-6675-2112
AD  - Department of Health Sciences, University of Leicester, Leicester, LE1 7RH, UK. 
      kaf19@leicester.ac.uk.
FAU - Demidov, German
AU  - Demidov G
AD  - Institute of Medical Genetics and Applied Genomics, University of Tubingen, 
      Tubingen, Germany.
FAU - Shrine, Nick
AU  - Shrine N
AD  - Department of Health Sciences, University of Leicester, Leicester, LE1 7RH, UK.
FAU - Paynton, Megan L
AU  - Paynton ML
AD  - Department of Health Sciences, University of Leicester, Leicester, LE1 7RH, UK.
FAU - Ossowski, Stephan
AU  - Ossowski S
AD  - Institute of Medical Genetics and Applied Genomics, University of Tubingen, 
      Tubingen, Germany.
FAU - Sayers, Ian
AU  - Sayers I
AD  - Translational Medical Sciences, NIHR Respiratory Biomedical Research Centre, 
      School of Medicine, Biodiscovery Institute, University of Nottingham, University 
      Park, Nottingham, UK.
FAU - Wain, Louise V
AU  - Wain LV
AD  - Department of Health Sciences, University of Leicester, Leicester, LE1 7RH, UK.
AD  - Leicester Respiratory Biomedical Research Centre, National Institute for Health 
      Research, Glenfield Hospital, Leicester, LE3 9QP, UK.
FAU - Hollox, Edward J
AU  - Hollox EJ
AD  - Department of Genetics and Genome Biology, University of Leicester, Leicester, 
      UK.
LA  - eng
GR  - MC_PC_17228/MRC_/Medical Research Council/United Kingdom
GR  - MC_QA137853/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220521
PL  - England
TA  - BMC Med Genomics
JT  - BMC medical genomics
JID - 101319628
RN  - 0 (Amino Acids)
RN  - 0 (HLA-DQ Antigens)
RN  - 0 (HLA-DRB1 Chains)
RN  - 0 (Histocompatibility Antigens Class I)
SB  - IM
MH  - Alleles
MH  - Amino Acids/genetics
MH  - *Asthma/genetics
MH  - Bayes Theorem
MH  - Biological Specimen Banks
MH  - *DNA Copy Number Variations
MH  - Exome
MH  - Genetic Predisposition to Disease
MH  - HLA-DQ Antigens/genetics
MH  - HLA-DRB1 Chains/genetics
MH  - Haplotypes
MH  - Histocompatibility Antigens Class I
MH  - Humans
MH  - United Kingdom
MH  - Exome Sequencing
PMC - PMC9124406
OTO - NOTNLM
OT  - Asthma
OT  - Copy number variants
OT  - Exome sequencing
OT  - Fine-mapping
OT  - Genetic association
OT  - Human leukocyte antigen
OT  - UK Biobank
COIS- LVW has research funding (outside of submitted work) from GSK and Orion Pharma 
      and consultancy for Galapagos. All other authors declare that they have no 
      competing interests.
EDAT- 2022/05/22 06:00
MHDA- 2022/05/25 06:00
PMCR- 2022/05/21
CRDT- 2022/05/21 23:36
PHST- 2022/02/27 00:00 [received]
PHST- 2022/05/10 00:00 [accepted]
PHST- 2022/05/21 23:36 [entrez]
PHST- 2022/05/22 06:00 [pubmed]
PHST- 2022/05/25 06:00 [medline]
PHST- 2022/05/21 00:00 [pmc-release]
AID - 10.1186/s12920-022-01268-y [pii]
AID - 1268 [pii]
AID - 10.1186/s12920-022-01268-y [doi]
PST - epublish
SO  - BMC Med Genomics. 2022 May 21;15(1):119. doi: 10.1186/s12920-022-01268-y.