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 etiology 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 (e.g. psoriasis, ankylosing spondylitis, type I diabetes, and celiac disease) with some having strong cross-phenotype associations potentially driven by pleiotropic effects. Importantly, novel associations with 8 diseases not previously assessed by GWAS (e.g., 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 etiologies. Conclusions These results demonstrate that the PheWAS approach is a powerful and novel method to discover SNP-disease associations, and is ideal when characterizing cross-phenotype associations, and further emphasizes the importance of the MHC region in human health and disease.

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

“…Previous investigations including GWAS have utilized a phenotype to genotype approach, which involves identifying individuals with a specific phenotype first and then determining genetic associations with that phenotype. The broader question of the influence of HLA variation in these genes across multiple human disease phenotypes has not been comprehensively investigated(7). …”

Genomic and Phenomic Research in the 21st Century

“…Two years later, multiple HLA genes, including HLA-DRB1 , were identified to be associated with rosacea by the first GWAS on this condition [66]. Comprehensive evaluations of all HLA genes by PheWAS have further emphasized the capacity of the PheWAS technique to quantify pleiotropy in this important region of the human genome [67–69].…”

“…It is expected that advancements in PheWAS will take a similar but perhaps not as linear a path. This is evident by the first PheWASs starting with candidate SNP studies [49] then quickly followed by candidate gene [52, 55, 84, 85] and multiple gene studies [67, 68, 86–88]. Although the PheWAS community is taking a similar path that other scientists took to reach GWAS, growth in PheWAS will always be limited by the availability of phenomic data.…”

Lichen planus

“…Contact allergens, such as mercury, copper and gold, have also been reported to be problematic (McParland & Warnakulasuriya, 2012). There appears to be a genetic predisposition, and an increased prevalence of lichen planus has been observed in individuals with HLA-DQB1, as well as other haplotypes (Liu et al., 2016). It is also thought that flares of the condition can be triggered by physical or emotional stress.…”