Fig. 2: Exome-wide analysis of rare genetic variation for 40 IMDs in UKB.

A Multiple-trait Manhattan plot representing the results from exome-wide gene-based tests for each IMDs. The red dotted line indicates the significance threshold at 2.5 × 10⁻⁶. SKAT P-values are two-sided and unadjusted. The significance threshold is set at FDR-corrected P-value < 0.05 for multiple comparisons. B Case-control enrichment of rare protein-coding variants in identified genes across consequence categories. The dot represents the OR; the putatively damaging nature of the variants reduces from dark blue to light blue according to the legend. C The number of predicted functional consequences, represented by color, that are displayed in risk-enhancing (OR > 1) and protective (OR < 1) associations. D Box plots of ORs in the five predicted functional consequences categories. Data are presented as median values, denoted by horizontal lines within boxes that represent the 25th and 75th percentiles, encompassing the interquartile range. Participant count: 350,770, encompassing a diverse cohort. Gene distribution is as follows: 90 genes with pLOF mutations; 45 genes with REVEL scores 75–100; 56 genes with scores 50–75; 60 genes with scores 25–50; and 50 genes with scores 0–25. IMD immune-mediated disease, UKB the United Kingdom Biobank, pLOF predicted loss-of-function, PC principal component, FDR false discovery rate, OR odds ratio, UR ultra-rare, R rare, pmis predicted deleterious missense, REVEL rare exome variant ensemble learner, RF rheumatic fever, AA alopecia areata, ACD allergic contact dermatitis, AD atopic dermatitis, AU allergic urticaria, Bullouse bullouse disorders, Lichen Lichen planus, SLE systemic lupus erythematosus, ADGC allergic and dietetic gastro-enteritis and colitis, Celiac celiac disease, Crohn Crohn’s disease, Hepatitis autoimmune hepatitis, PBC primary biliary cirrhosis, UC ulcerative colitis, T1D diabetes mellitus (Type I), Graves Graves’ disease, HPT autoimmune hypothyroidism, AP allergic purpura, ID immunodeficiency with predominantly antibody defects, ITP idiopathic thrombocytopenic purpura, PA pernicious anemia, SD sarcoidosis, AS ankylosing spondylitis, Behcet Behcet’s disease, NV necrotizing vasculopathies, OA osteoarthritis, PR polymyalgia rheumatica, PST psoriatic and enteropathic arthropathies, Sicca Sicca syndrome (Sjogren’s syndrome); GB Guillain-Barre syndrome, MG myasthenia gravis, MS multiple sclerosis, AR allergic rhinitis.