PMID- 37923823
OWN - NLM
STAT- MEDLINE
DCOM- 20231106
LR  - 20231106
IS  - 2399-3642 (Electronic)
IS  - 2399-3642 (Linking)
VI  - 6
IP  - 1
DP  - 2023 Nov 3
TI  - HLA allele-calling using multi-ancestry whole-exome sequencing from the UK 
      Biobank identifies 129 novel associations in 11 autoimmune diseases.
PG  - 1113
LID - 10.1038/s42003-023-05496-5 [doi]
LID - 1113
AB  - The human leukocyte antigen (HLA) region on chromosome 6 is strongly associated 
      with many immune-mediated and infection-related diseases. Due to its highly 
      polymorphic nature and complex linkage disequilibrium patterns, traditional 
      genetic association studies of single nucleotide polymorphisms do not perform 
      well in this region. Instead, the field has adopted the assessment of the 
      association of HLA alleles (i.e., entire HLA gene haplotypes) with disease. Often 
      based on genotyping arrays, these association studies impute HLA alleles, 
      decreasing accuracy and thus statistical power for rare alleles and in 
      non-European ancestries. Here, we use whole-exome sequencing (WES) from 454,824 
      UK Biobank (UKB) participants to directly call HLA alleles using the HLA-HD 
      algorithm. We show this method is more accurate than imputing HLA alleles and 
      harness the improved statistical power to identify 360 associations for 11 
      auto-immune phenotypes (at least 129 likely novel), leading to better insights 
      into the specific coding polymorphisms that underlie these diseases. We show that 
      HLA alleles with synonymous variants, often overlooked in HLA studies, can 
      significantly influence these phenotypes. Lastly, we show that HLA sequencing may 
      improve polygenic risk scores accuracy across ancestries. These findings allow 
      better characterization of the role of the HLA region in human disease.
CI  - (c) 2023. The Author(s).
FAU - Butler-Laporte, Guillaume
AU  - Butler-Laporte G
AUID- ORCID: 0000-0001-5388-0396
AD  - Department of Epidemiology, Biostatistics and Occupational Health, McGill 
      University, Montreal, QC, Canada. guillaume.butler-laporte@mcgill.ca.
AD  - Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, 
      Canada. guillaume.butler-laporte@mcgill.ca.
AD  - Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. 
      guillaume.butler-laporte@mcgill.ca.
FAU - Farjoun, Joseph
AU  - Farjoun J
AD  - Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, 
      Canada.
FAU - Nakanishi, Tomoko
AU  - Nakanishi T
AUID- ORCID: 0000-0001-9510-5646
AD  - Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, 
      Canada.
AD  - Kyoto-McGill International Collaborative School in Genomic Medicine, Graduate 
      School of Medicine, Kyoto University, Kyoto, Japan.
AD  - Department of Human Genetics, McGill University, Montreal, QC, Canada.
AD  - Research Fellow, Japan Society for the Promotion of Science, Tokyo, Japan.
FAU - Lu, Tianyuan
AU  - Lu T
AUID- ORCID: 0000-0002-5664-5698
AD  - Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, 
      Canada.
AD  - 5 Prime Sciences Inc, Montreal, Quebec, Canada.
FAU - Abner, Erik
AU  - Abner E
AUID- ORCID: 0000-0002-6529-3161
AD  - Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, 
      Estonia.
FAU - Chen, Yiheng
AU  - Chen Y
AD  - Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, 
      Canada.
FAU - Hultstrom, Michael
AU  - Hultstrom M
AUID- ORCID: 0000-0003-4675-1099
AD  - Department of Epidemiology, Biostatistics and Occupational Health, McGill 
      University, Montreal, QC, Canada.
AD  - Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, 
      Canada.
AD  - Integrative Physiology, Department of Medical Cell Biology, Uppsala University, 
      Uppsala, Sweden.
AD  - Anaesthesiology and Intensive Care Medicine, Department of Surgical Sciences, 
      Uppsala University, Uppsala, Sweden.
FAU - Metspalu, Andres
AU  - Metspalu A
AUID- ORCID: 0000-0002-3718-796X
AD  - Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, 
      Estonia.
FAU - Milani, Lili
AU  - Milani L
AUID- ORCID: 0000-0002-5323-3102
AD  - Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, 
      Estonia.
FAU - Magi, Reedik
AU  - Magi R
AUID- ORCID: 0000-0002-2964-6011
AD  - Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, 
      Estonia.
FAU - Nelis, Mari
AU  - Nelis M
AD  - Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, 
      Estonia.
FAU - Hudjashov, Georgi
AU  - Hudjashov G
AD  - Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, 
      Estonia.
CN  - Estonian Biobank Research Team
FAU - Yoshiji, Satoshi
AU  - Yoshiji S
AD  - Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, 
      Canada.
AD  - Kyoto-McGill International Collaborative School in Genomic Medicine, Graduate 
      School of Medicine, Kyoto University, Kyoto, Japan.
AD  - Department of Human Genetics, McGill University, Montreal, QC, Canada.
AD  - Research Fellow, Japan Society for the Promotion of Science, Tokyo, Japan.
FAU - Ilboudo, Yann
AU  - Ilboudo Y
AD  - Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, 
      Canada.
FAU - Liang, Kevin Y H
AU  - Liang KYH
AD  - Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, 
      Canada.
FAU - Su, Chen-Yang
AU  - Su CY
AUID- ORCID: 0000-0001-6071-4660
AD  - Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, 
      Canada.
FAU - Willet, Julian D S
AU  - Willet JDS
AUID- ORCID: 0000-0002-8103-0329
AD  - Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, 
      Canada.
FAU - Esko, Tonu
AU  - Esko T
AD  - Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, 
      Estonia.
FAU - Zhou, Sirui
AU  - Zhou S
AD  - Department of Human Genetics, McGill University, Montreal, QC, Canada.
FAU - Forgetta, Vincenzo
AU  - Forgetta V
AD  - Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, 
      Canada.
AD  - 5 Prime Sciences Inc, Montreal, Quebec, Canada.
FAU - Taliun, Daniel
AU  - Taliun D
AD  - Department of Human Genetics, McGill University, Montreal, QC, Canada.
FAU - Richards, J Brent
AU  - Richards JB
AUID- ORCID: 0000-0002-3746-9086
AD  - Department of Epidemiology, Biostatistics and Occupational Health, McGill 
      University, Montreal, QC, Canada.
AD  - Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, 
      Canada.
AD  - Department of Human Genetics, McGill University, Montreal, QC, Canada.
AD  - 5 Prime Sciences Inc, Montreal, Quebec, Canada.
AD  - Department of Twin Research, King's College London, London, UK.
AD  - Infectious Diseases and Immunity in Global Health Program, Research Institute of 
      the McGill University Health Centre, Montreal, Quebec, Canada.
LA  - eng
GR  - C18281/A29019/CRUK_/Cancer Research UK/United Kingdom
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20231103
PL  - England
TA  - Commun Biol
JT  - Communications biology
JID - 101719179
RN  - 0 (HLA Antigens)
RN  - 0 (Histocompatibility Antigens Class I)
RN  - 0 (Histocompatibility Antigens Class II)
SB  - IM
MH  - Humans
MH  - Alleles
MH  - *Biological Specimen Banks
MH  - Exome Sequencing
MH  - Genetic Predisposition to Disease
MH  - *Autoimmune Diseases/genetics
MH  - HLA Antigens/genetics
MH  - Histocompatibility Antigens Class I/genetics
MH  - Histocompatibility Antigens Class II
MH  - Polymorphism, Single Nucleotide
MH  - United Kingdom
PMC - PMC10624861
COIS- The authors declare the following competing interests: JBR's institution has 
      received investigator-initiated grant funding from Eli Lilly, GlaxoSmithKline and 
      Biogen for projects unrelated to this research. He is the CEO of 5 Prime Sciences 
      Inc (www.5primesciences.com). J.F., T.L., and V.F. are employees of 5 Prime 
      Sciences Inc. T.N. has received a speaking fee from Boehringer Ingelheim for 
      talks unrelated to this research. The other authors declare no competing 
      interests.
EDAT- 2023/11/04 21:46
MHDA- 2023/11/06 06:42
PMCR- 2023/11/03
CRDT- 2023/11/04 00:30
PHST- 2023/06/09 00:00 [received]
PHST- 2023/10/20 00:00 [accepted]
PHST- 2023/11/06 06:42 [medline]
PHST- 2023/11/04 21:46 [pubmed]
PHST- 2023/11/04 00:30 [entrez]
PHST- 2023/11/03 00:00 [pmc-release]
AID - 10.1038/s42003-023-05496-5 [pii]
AID - 5496 [pii]
AID - 10.1038/s42003-023-05496-5 [doi]
PST - epublish
SO  - Commun Biol. 2023 Nov 3;6(1):1113. doi: 10.1038/s42003-023-05496-5.