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Sci Transl Med. 2017 May 10;9(389). pii: eaai8708. doi: 10.1126/scitranslmed.aai8708.

Phenome-wide scanning identifies multiple diseases and disease severity phenotypes associated with HLA variants.

Author information

1
Department of Pharmacy Practice and Science, University of Arizona College of Pharmacy, Tucson, AZ 85721, USA.
2
Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
3
Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
4
School of Anatomy, Physiology and Human Biology, University of Western Australia, Nedlands, Western Australia, Australia.
5
Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
6
Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia.
7
Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
8
Center for Quantitative Sciences, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
9
Division of Rheumatology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
10
Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
11
Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
12
Partners Center for Personalized Genetic Medicine, Boston, MA 02115, USA.
13
Institute of Inflammation and Repair, University of Manchester, Manchester, UK.
14
Department of Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden.
15
Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
16
Biomedical Informatics Research Center, Marshfield Clinic Research Foundation, Marshfield, WI 54449, USA.
17
Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WI 54449, USA.
18
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
19
Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. josh.denny@vanderbilt.edu.

Abstract

Although many phenotypes have been associated with variants in human leukocyte antigen (HLA) genes, the full phenotypic impact of HLA variants across all diseases is unknown. We imputed HLA genomic variation from two populations of 28,839 and 8431 European ancestry individuals and tested association of HLA variation with 1368 phenotypes. A total of 104 four-digit and 92 two-digit HLA allele phenotype associations were significant in both discovery and replication cohorts, the strongest being HLA-DQB1*03:02 and type 1 diabetes. Four previously unidentified associations were identified across the spectrum of disease with two- and four-digit HLA alleles and 10 with nonsynonymous variants. Some conditions associated with multiple HLA variants and stronger associations with more severe disease manifestations were identified. A comprehensive, publicly available catalog of clinical phenotypes associated with HLA variation is provided. Examining HLA variant disease associations in this large data set allows comprehensive definition of disease associations to drive further mechanistic insights.

PMID:
28490672
PMCID:
PMC5563969
DOI:
10.1126/scitranslmed.aai8708
[Indexed for MEDLINE]
Free PMC Article

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