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Original article
Phenome-wide association study maps new diseases to the human major histocompatibility complex region
  1. Jixia Liu1,
  2. Zhan Ye2,
  3. John G Mayer2,
  4. Brian A Hoch2,
  5. Clayton Green3,
  6. Loren Rolak4,
  7. Christopher Cold5,
  8. Seik-Soon Khor6,
  9. Xiuwen Zheng7,
  10. Taku Miyagawa6,8,
  11. Katsushi Tokunaga6,
  12. Murray H Brilliant1,
  13. Scott J Hebbring1
  1. 1Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, Wisconsin, USA
  2. 2Biomedical Informatics Research Center, Marshfield Clinic Research Foundation, Marshfield, Wisconsin, USA
  3. 3Department of Dermatology, Marshfield Clinic, Marshfield, Wisconsin, USA
  4. 4Department of Neurology, Marshfield Clinic, Marshfield, Wisconsin, USA
  5. 5Department of Pathology, Marshfield Clinic, Marshfield, Wisconsin, USA
  6. 6Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
  7. 7Department of Biostatistics, University of Washington, Seattle, Washington, USA
  8. 8Sleep Disorders Project, Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
  1. Correspondence to Dr Scott J Hebbring, Marshfield Clinic Research Foundation, Center for Human Genetics, 1000 N Oak Ave, Marshfield, WI 54449, USA; hebbring.scott{at}


Background Over 160 disease phenotypes have been mapped to the major histocompatibility complex (MHC) region on chromosome 6 by genome-wide association study (GWAS), suggesting that the MHC region as a whole may be involved in the aetiology of many phenotypes, including unstudied diseases. The phenome-wide association study (PheWAS), a powerful and complementary approach to GWAS, has demonstrated its ability to discover and rediscover genetic associations. The objective of this study is to comprehensively investigate the MHC region by PheWAS to identify new phenotypes mapped to this genetically important region.

Methods In the current study, we systematically explored the MHC region using PheWAS to associate 2692 MHC-linked variants (minor allele frequency ≥0.01) with 6221 phenotypes in a cohort of 7481 subjects from the Marshfield Clinic Personalized Medicine Research Project.

Results Findings showed that expected associations previously identified by GWAS could be identified by PheWAS (eg, psoriasis, ankylosing spondylitis, type I diabetes and coeliac disease) with some having strong cross-phenotype associations potentially driven by pleiotropic effects. Importantly, novel associations with eight diseases not previously assessed by GWAS (eg, lichen planus) were also identified and replicated in an independent population. Many of these associated diseases appear to be immune-related disorders. Further assessment of these diseases in 16 484 Marshfield Clinic twins suggests that some of these diseases, including lichen planus, may have genetic aetiologies.

Conclusions These results demonstrate that the PheWAS approach is a powerful and novel method to discover SNP–disease associations, and is ideal when characterising cross-phenotype associations, and further emphasise the importance of the MHC region in human health and disease.

  • phenome-wide association study (PheWAS)
  • Genome-Wide Association Study (GWAS)
  • HLA
  • major histocompatibility complex (MHC)
  • Precision Medicine

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