Phenome-wide association study maps new diseases to the human major histocompatibility complex region.
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.



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.



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.



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.
Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, Wisconsin, USA.
Jixia
J
Liu
Biomedical Informatics Research Center, Marshfield Clinic Research Foundation, Marshfield, Wisconsin, USA.
Zhan
Z
Ye
Biomedical Informatics Research Center, Marshfield Clinic Research Foundation, Marshfield, Wisconsin, USA.
John G
JG
Mayer
Biomedical Informatics Research Center, Marshfield Clinic Research Foundation, Marshfield, Wisconsin, USA.
Brian A
BA
Hoch
Department of Dermatology, Marshfield Clinic, Marshfield, Wisconsin, USA.
Clayton
C
Green
Department of Neurology, Marshfield Clinic, Marshfield, Wisconsin, USA.
Loren
L
Rolak
Department of Pathology, Marshfield Clinic, Marshfield, Wisconsin, USA.
Christopher
C
Cold
Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Seik-Soon
SS
Khor
Department of Biostatistics, University of Washington, Seattle, Washington, USA.
Xiuwen
X
Zheng
Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan Sleep Disorders Project, Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
Taku
T
Miyagawa
Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Katsushi
K
Tokunaga
Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, Wisconsin, USA.
Murray H
MH
Brilliant
Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, Wisconsin, USA.
Scott J
SJ
Hebbring
D000328:Adult; D000368:Aged; D002896:Chromosomes, Human, Pair 6; D005260:Female; D056726:Genetic Association Studies / Q000379:methods*; D006801:Humans; D007154:Immune System Diseases / Q000235:genetics*; D007249:Inflammation / Q000235:genetics*; D008010:Lichen Planus / Q000235:genetics; D008285:Major Histocompatibility Complex; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D044465:White People / Q000235:genetics
Genome-Wide Association Study (GWAS); HLA; Precision Medicine; major histocompatibility complex (MHC); phenome-wide association study (PheWAS)