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

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.

Figure 1

Association of all imputed four digit HLA alleles with PheWAS phenotypes by HLA locus. HLA alleles were imputed form HumanExome BeadChip using SNP2HLA. Odds ratios, 95% confidence intervals and p values were generated using a χ² distribution or Fisher’s Exact Test. Strength of the association is plotted along the y axis as –log(p) and phenotypes are represented on the x axis categorized by PheWAS code group. AS indicates Ankylosing spondylitis; Acute bronchitis and bronchiolitis (Bronch.); Celiac disease (CeD); Cholangitis (Cholang.); Circulatory disease (CircDis); Degenerative and vascular disorders of ear (EarDis); Dermatomyositis (Derm); Diabetes mellitus (DM); Diabetic retinopathy (DR); Diffuse diseases of connective tissue (CTDis); Disorders of other cranial nerves (CNDis); Graves’ disease (GD); Hypothyroidism (HypoTh); Ileostomy status (Ileost.); Inflammatory bowel disease and other gastroenteritis and colitis (IBD); Juvenile rheumatoid arthritis (JuvRA); Lack of coordination (LOC); Loss of teeth or edentulism (Tooth loss); Lupus, localized and systemic (Lupus); Multiple sclerosis (MS); Other demyelinating diseases of central nervous system (CNSDis); Other endocrine disorders (Endocrine); Other inflammatory spondylopathies (Spondyl.); Polymyalgia Rheumatica (PR); Posttraumatic wound infection (Wound inf.); Primary biliary cirrhosis (PBC); Psoriasis and related disorders (Psoriasis*); Psoriasis vulgaris (PsoriasisV); Rheumatoid arthritis (RA); Rheumatoid arthritis and other inflammatory polyarthropathies (RA*); Secondary malignant neoplasm of digestive systems (2o neopl.); Sicca syndrome (SS); Systemic Lupus erythematosus (SLE); Type 1 diabetes (T1D); Type 1 diabetes with ketoacidosis (T1DK); Type 1 diabetes with neurological manifestations (T1DN); Type 1 diabetes with ophthalmic manifestations (T1DO); Type 1 diabetes with renal manifestations (T1DR); Thyrotoxicosis with or without goiter (Thyrotox.); Uveitis, noninfectious or not otherwise specified (Uveitis).

Figure 2

Heatmap of four digit HLA allelic associations with p<1×10⁻⁵. Red indicates an increased odds ratio and blue indicates a decreased odd ratio. Phenotypes and HLA alleles are clustered by similarity based on association results. Carats indicate groupings that were present in over 90% of 1,000 bootstrap simulations, calculated from sampling with replacement from the actual association results.

Figure 3

Network diagram of 171 PheWAS analysis associations between four-digit HLA alleles and PheWAS codes at p<1×10⁻⁵. Large circular nodes indicate HLA genes, small circular nodes represent four digit HLA alleles and colored squares represent PheWAS phenotypes. Lines indicate an association and distance between nodes indicates the strength of the association by p value. Dashed lines represent a protective effect (OR <1) and solid lines indicate a risk effect (OR >1). The shade of the lines indicated three different levels of statistical significances based on P values, with the darkest level for the most significant associations at p<1 × 10⁻¹⁵, the intermediate level for the significances at p value between 1 × 10⁻⁸ and 1 × 10⁻¹⁵ and the light level for those at p<1⁻⁵. An interactive version is available at http://phewascatalog.org. AS indicates Ankylosing spondylitis; Celiac disease (CeD); Circulatory Disease (CirDis); Degenerative and vascular disorders of ear (EarDis); Dermatomyositis (Derm); Diabetes mellitus (DM); Diabetic retinopathy (DR); Diffuse diseases of connective tissue (CTDis); Disorders of other cranial nerves (CNDis); Other endocrine disorders (EndoDis); Graves’ disease (GD); Hypothyroidism (HypoTh); Hypothyroidism NOS (HypoTh*); Ileostomy Status (Ileostomy); Insulin pump user (T1Dins); Juvenile rheumatoid arthritis (JuvRA); Lack of coordination (LOC); Multiple sclerosis (MS); Noninflammatory disorders of cervix (CervixDis); Other demyelinating diseases of central nervous system (CNSDis); Other inflammatory spondylopathies (Spondyl.); Polymyalgia Rheumatica (PR); Primary biliary cirrhosis (PBC); Psoriasis and related disorders (Psoriasis*); Psoriasis vulgaris (PsoriasisV); Rheumatoid arthritis (RA); Rheumatoid arthritis and other inflammatory polyarthropathies (RA*); Sicca syndrome (SS); Type 1 diabetes (T1D); Type 1 diabetes with ketoacidosis (T1DK); Type 1 diabetes with neurological manifestations (T1DN); Type 1 diabetes with ophthalmic manifestations (T1DO); Type 1 diabetes with renal manifestations (T1DR); Ulcerative colitis (UC)