Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Liu J

PROVIDER: S-EPMC5035188 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Liu Jixia J Ye Zhan Z Mayer John G JG Hoch Brian A BA Green Clayton C Rolak Loren L Cold Christopher C Khor Seik-Soon SS Zheng Xiuwen X Miyagawa Taku T Tokunaga Katsushi K Brilliant Murray H MH Hebbring Scott J SJ

Journal of medical genetics 20160610 10

<h4>Background</h4>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 ...[more]

PMID: 27287392

Similar Datasets

Project description:Infectious diseases cause tremendous financial losses in the pork industry, emphasizing the importance of disease resilience, which is the ability of an animal to maintain performance under disease. Previously, a natural polymicrobial disease challenge model was established, in which pigs were challenged in the late nursery phase by multiple pathogens to maximize expression of genetic differences in disease resilience. Genetic analysis found that performance traits in this model, including growth rate, feed and water intake, and carcass traits, as well as clinical disease phenotypes, were heritable and could be selected for to increase disease resilience of pigs. The objectives of the current study were to identify genomic regions that are associated with disease resilience in this model, using genome-wide association studies and fine-mapping methods, and to use gene set enrichment analyses to determine whether genomic regions associated with disease resilience are enriched for previously published quantitative trait loci, functional pathways, and differentially expressed genes subject to physiological states. Multiple quantitative trait loci were detected for all recorded performance and clinical disease traits. The major histocompatibility complex region was found to explain substantial genetic variance for multiple traits, including for growth rate in the late nursery (12.8%) and finisher (2.7%), for several clinical disease traits (up to 2.7%), and for several feeding and drinking traits (up to 4%). Further fine mapping identified 4 quantitative trait loci in the major histocompatibility complex region for growth rate in the late nursery that spanned the subregions for class I, II, and III, with 1 single-nucleotide polymorphism in the major histocompatibility complex class I subregion capturing the largest effects, explaining 0.8-27.1% of genetic variance for growth rate and for multiple clinical disease traits. This single-nucleotide polymorphism was located in the enhancer of TRIM39 gene, which is involved in innate immune response. The major histocompatibility complex region was pleiotropic for growth rate in the late nursery and finisher, and for treatment and mortality rates. Growth rate in the late nursery showed strong negative genetic correlations in the major histocompatibility complex region with treatment or mortality rates (-0.62 to -0.85) and a strong positive genetic correlation with growth rate in the finisher (0.79). Gene set enrichment analyses found genomic regions associated with resilience phenotypes to be enriched for previously identified disease susceptibility and immune capacity quantitative trait loci, for genes that were differentially expressed following bacterial or virus infection and immune response, and for gene ontology terms related to immune and inflammatory response. In conclusion, the major histocompatibility complex and other quantitative trait loci that harbor immune-related genes were identified to be associated with disease resilience traits in a large-scale natural polymicrobial disease challenge. The major histocompatibility complex region was pleiotropic for growth rate under challenge and for clinical disease traits. Four quantitative trait loci were identified across the class I, II, and III subregions of the major histocompatibility complex for nursery growth rate under challenge, with 1 single-nucleotide polymorphism in the major histocompatibility complex class I subregion capturing the largest effects. The major histocompatibility complex and other quantitative trait loci identified play an important role in host response to infectious diseases and can be incorporated in selection to improve disease resilience, in particular the identified single-nucleotide polymorphism in the major histocompatibility complex class I subregion.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets