Disease Clusters?

Groups of diseases that share a large number of curated genes with each other, computed via label propagation over the shared-gene similarity graph. See also Shared-Gene Disease Pairs for pairwise comparisons.

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Cluster 142

9 diseases · 13 shared-gene connections
9 Diseases
392 Unique genes
0.121 Avg. similarity score
Common variable immunodeficiency Most-connected disease (7 links)
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Disease Searched: immunodeficiency, common variable, 4 Pinned (dragged)
Node size = connections within this cluster · edge thickness = similarity strength · hover an edge for its details · click a node to select it and show its pairs below (double-click or Ctrl/⌘-click opens the disease page) · drag a node to pin it in place · scroll/pinch to zoom.

Member diseases (most connected first ‐ the cluster's core)

Disease ⇵ Connections in cluster ⇵ Significant partners ⇵ Curated genes ⇵
Common variable immunodeficiency 7 7 75
Autoimmune disease 4 4 202
Autoimmune thyroid disease 4 4 144
Celiac disease 4 4 193
isolated sulfite oxidase deficiency 3 3 1
Autoinflammation with pulmonary and cutaneous vasculitis 1 1 1
immunodeficiency, common variable, 4 1 1 1
immunodeficiency, common variable, 6 1 1 1
immunodeficiency, common variable, 7 1 1 1

Top shared genes (genes linked to 2+ member diseases ‐ top 100 shown, download for all)

Gene ⇵ Member diseases ⇵ Linked diseases
SUOX 5 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency and 1 more
ADCY7 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
ADGRL2 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
ANKRD55 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
ATG16L1 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
ATXN2L 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
C1ORF141 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
CARD9 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
CRB1 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
CYTL1 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
DAG1 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
DCTD 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
ERAP2 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
FNBP1 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
FUT2 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
GPR35 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
GSDMB 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
HLA-DQB1 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
ICOS 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
IGF2 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
IL10 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
IL18RAP 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
IL23R 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
IL2RA 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
INS-IGF2 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
IRF1 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
JAK2 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
KEAP1 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
LRRK2 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
LURAP1L 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
NKD1 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
NKX2-3 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
NPIPB6 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
PDE4A 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
PHTF1 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
RSBN1 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
SBK1 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
SLC25A28 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
SLC9A4 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
SMAD3 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
STMN3 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
TENM3 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
TNFSF15 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
TTC33 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
ZMIZ1 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
ZPBP2 4 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease, Common variable immunodeficiency
BACH2 3 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease
CTLA4 3 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease
ELMO1 3 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease
IRF4 3 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease
LPP 3 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease
MMEL1 3 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease
PSMB9 3 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease
PTPN2 3 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease
SH2B3 3 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease
STAT4 3 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease
TNFRSF14 3 / 9 Autoimmune disease, Autoimmune thyroid disease, Celiac disease
AFF3 2 / 9 Autoimmune disease, Celiac disease
ARHGAP31 2 / 9 Autoimmune disease, Celiac disease
ARID5B 2 / 9 Autoimmune disease, Autoimmune thyroid disease
ATXN2 2 / 9 Autoimmune thyroid disease, Celiac disease
BANF2 2 / 9 Autoimmune disease, Autoimmune thyroid disease
BTNL2 2 / 9 Autoimmune thyroid disease, Celiac disease
C12ORF42 2 / 9 Autoimmune disease, Autoimmune thyroid disease
C1QTNF6 2 / 9 Autoimmune disease, Autoimmune thyroid disease
CAMK4 2 / 9 Autoimmune disease, Autoimmune thyroid disease
CBLB 2 / 9 Autoimmune disease, Autoimmune thyroid disease
CCL21 2 / 9 Autoimmune disease, Celiac disease
CCN4 2 / 9 Autoimmune disease, Autoimmune thyroid disease
CD226 2 / 9 Autoimmune disease, Autoimmune thyroid disease
CD247 2 / 9 Autoimmune thyroid disease, Celiac disease
CD28 2 / 9 Autoimmune disease, Celiac disease
CD40LG 2 / 9 Autoimmune disease, Common variable immunodeficiency
CD81 2 / 9 Common variable immunodeficiency, immunodeficiency, common variable, 6
CR2 2 / 9 Common variable immunodeficiency, immunodeficiency, common variable, 7
CTSH 2 / 9 Autoimmune disease, Celiac disease
CXCR5 2 / 9 Autoimmune disease, Celiac disease
DNASE1L3 2 / 9 Autoimmune disease, Autoimmune thyroid disease
ERBB3 2 / 9 Autoimmune disease, Autoimmune thyroid disease
FAM76B 2 / 9 Autoimmune disease, Autoimmune thyroid disease
FASLG 2 / 9 Autoimmune disease, Celiac disease
FLT3 2 / 9 Autoimmune disease, Autoimmune thyroid disease
GIGYF1 2 / 9 Autoimmune disease, Autoimmune thyroid disease
HCK 2 / 9 Autoimmune disease, Autoinflammation with pulmonary and cutaneous vasculitis
HLA-B 2 / 9 Autoimmune disease, Celiac disease
HLA-DOA 2 / 9 Autoimmune disease, Celiac disease
HLA-DPA1 2 / 9 Autoimmune disease, Celiac disease
HLA-DQA1 2 / 9 Autoimmune thyroid disease, Celiac disease
HLA-DRA 2 / 9 Autoimmune thyroid disease, Celiac disease
HLA-DRB1 2 / 9 Autoimmune thyroid disease, Celiac disease
IFNG 2 / 9 Autoimmune disease, Celiac disease
IKZF1 2 / 9 Autoimmune disease, Common variable immunodeficiency
IL21 2 / 9 Celiac disease, Common variable immunodeficiency
IL6 2 / 9 Autoimmune disease, Celiac disease
JAK1 2 / 9 Autoimmune disease, Autoimmune thyroid disease
MACIR 2 / 9 Autoimmune disease, Autoimmune thyroid disease
MBL2 2 / 9 Autoimmune thyroid disease, Common variable immunodeficiency
PLEKHA1 2 / 9 Autoimmune disease, Autoimmune thyroid disease
PPARG 2 / 9 Autoimmune disease, Autoimmune thyroid disease
PRRC2A 2 / 9 Autoimmune disease, Celiac disease
What do these columns mean?
Connections in cluster
How many other members this disease has a shared-gene link to (the node size in the network above). The most-connected diseases are the cluster's core.
Significant partners
How many of those links are statistically significant (FDR q < 0.05).
Curated genes
Distinct curated genes linked to that disease in GeDiPNet.
Member diseases (Top shared genes)
How many of this cluster's diseases are linked to the gene, out of the cluster's total. Genes shared by many members are the most direct explanation of why they group together.
Overlap genes (x / y)
x = genes shared between this cluster and the pathway/GO term; y = that pathway/GO term's total gene count. A higher x relative to y (and to the cluster's own size) means a tighter biological match.
Cluster gene count
Total distinct genes across every disease in this cluster -- the "n" used in the significance test below.
Fold enrichment
Observed overlap divided by the overlap expected by chance, given the cluster's gene count, the pathway/term's size and the gene universe tested. 5× means five times more shared genes than random. Tells strong hits apart when q-values are all vanishingly small.
P-value / FDR q-value
Is this pathway/GO term's overlap with the cluster more than chance? Upper-tail hypergeometric test, Benjamini-Hochberg corrected across every tested pathway/term (prefer the q-value -- it accounts for testing many at once).
Shared genes (Pairs within this cluster)
Number of curated genes the two diseases in that row have in common.
Similarity score (Pairs within this cluster)
Jaccard-based gene overlap between the two specific diseases in that row -- same metric as the main Shared-Gene Disease Pairs page.

Enriched Pathways (why this cluster is grouped, biologically)

Pathway ⇵ Source ⇵ Overlap genes ⇵ Fold enrichment ⇵ P-value ⇵ FDR q-value ⇵
Intestinal immune network for IgA production
CD28, HLA-DMB, HLA-DOA, HLA-DPA1, HLA-DQB1, ICOS, IL10, AICDA, CD40LG, IL4, IL6, CD86
 KEGG 26 / 50 15.9× 5.95e-26 1.14e-22 ✓ sig.
Inflammatory bowel disease
GATA3, HLA-DMB, HLA-DOA, HLA-DPA1, HLA-DQB1, IL10, IL18RAP, IL23R, SMAD3, STAT4, STAT3, IFNG
 KEGG 28 / 66 13.0× 1.03e-24 1.60e-21 ✓ sig.
Th17 cell differentiation
GATA3, HLA-DMB, HLA-DOA, HLA-DPA1, HLA-DQB1, IL23R, IL2RA, IRF4, JAK1, JAK2, SMAD3, TYK2
 KEGG 32 / 109 9.0× 3.01e-22 3.28e-19 ✓ sig.
Autoimmune thyroid disease
CD28, CTLA4, FASLG, HLA-B, HLA-DMB, HLA-DOA, HLA-DPA1, HLA-DQB1, IL10, TG, TPO, CD40LG
 KEGG 24 / 54 13.6× 6.09e-22 6.04e-19 ✓ sig.
Allograft rejection
CD28, FASLG, HLA-B, HLA-DMB, HLA-DOA, HLA-DPA1, HLA-DQB1, IL10, CD40LG, FAS, IFNG, IL4
 KEGG 21 / 39 16.5× 1.32e-21 1.17e-18 ✓ sig.
Graft-versus-host disease
CD28, FASLG, HLA-B, HLA-DMB, HLA-DOA, HLA-DPA1, HLA-DQB1, FAS, IFNG, IL6, CD86, HLA-DQA1
 KEGG 19 / 45 12.9× 4.20e-17 1.80e-14 ✓ sig.
Th1 and Th2 cell differentiation
GATA3, HLA-DMB, HLA-DOA, HLA-DPA1, HLA-DQB1, IL2RA, JAK1, JAK2, STAT4, TYK2, ZAP70, IFNG
 KEGG 25 / 93 8.2× 1.29e-16 5.15e-14 ✓ sig.
Type I diabetes mellitus
CD28, FASLG, HLA-B, HLA-DMB, HLA-DOA, HLA-DPA1, HLA-DQB1, FAS, IFNG, CD86, HLA-DQA1, HLA-DRA
 KEGG 18 / 44 12.5× 5.69e-16 2.08e-13 ✓ sig.
Cytokine-cytokine receptor interaction
CCL21, CXCR5, FASLG, IL10, IL18RAP, IL23R, IL2RA, TNFRSF11B, TNFRSF14, TNFSF15, CD40LG, CXCR3
 KEGG 41 / 298 4.2× 3.54e-15 1.13e-12 ✓ sig.
Herpes simplex virus 1 infection
CARD9, FASLG, HLA-B, HLA-DMB, HLA-DOA, HLA-DPA1, HLA-DQB1, ITGB3, JAK1, JAK2, TAP1, TICAM1
 KEGG 31 / 182 5.2× 2.71e-14 7.27e-12 ✓ sig.
Toxoplasmosis
HLA-DMB, HLA-DOA, HLA-DPA1, HLA-DQB1, IL10, JAK1, JAK2, SOCS1, TYK2, STAT3, CD40LG, IFNG
 KEGG 24 / 112 6.6× 1.31e-13 3.12e-11 ✓ sig.
Primary immunodeficiency
ICOS, TAP1, ZAP70, AICDA, CD40LG, IL7R, TAP2, CIITA, BTK, CD19, DCLRE1C, IKBKG
 KEGG 15 / 38 12.1× 3.04e-13 6.78e-11 ✓ sig.
Interferon gamma signaling
HLA-B, HLA-DPA1, HLA-DQB1, IRF1, IRF4, IRF5, JAK1, JAK2, SOCS1, B2M, IFNG, HLA-DQA1
 Reactome 21 / 87 7.4× 3.79e-13 8.24e-11 ✓ sig.
Rheumatoid arthritis
CD28, CTLA4, HLA-DMB, HLA-DOA, HLA-DPA1, HLA-DQB1, IFNG, IL17A, IL6, TGFB2, CD86, HLA-DQA1
 KEGG 21 / 95 6.8× 2.41e-12 4.57e-10 ✓ sig.
Epstein-Barr virus infection
HLA-B, HLA-DMB, HLA-DOA, HLA-DPA1, HLA-DQB1, JAK1, TAP1, TNFAIP3, TYK2, STAT3, B2M, FAS
 KEGG 30 / 204 4.5× 3.74e-12 6.89e-10 ✓ sig.

Enriched GO Terms (Biological Process, a second line of biological evidence)

GO term ⇵ GO ID ⇵ Overlap genes ⇵ Fold enrichment ⇵ P-value ⇵ FDR q-value ⇵
immune response
CBLB, CCL21, CD28, CTLA4, CTSH, CXCR5, FASLG, HLA-B, HLA-DMB, HLA-DOA, HLA-DPA1, HLA-DQB1
 GO:0006955 72 / 543 6.3× 4.39e-37 3.74e-33 ✓ sig.
immune system process
CAMK4, CARD9, CD28, CTLA4, ERAP2, GATA3, HLA-B, HLA-DMB, HLA-DOA, HLA-DPA1, HLA-DQB1, IL18RAP
 GO:0002376 86 / 943 4.3× 6.64e-32 3.93e-28 ✓ sig.
positive regulation of T cell proliferation
CCDC88B, CD28, HLA-DMB, HLA-DPA1, IL23R, IL2RA, JAK2, TYK2, CD274, CD40LG, IL4, IL6
 GO:0042102 20 / 67 14.2× 3.96e-18 4.78e-15 ✓ sig.
inflammatory response
CAMK4, CCL21, GATA3, IL18RAP, IL23R, IL2RA, IRF5, MACIR, TICAM1, TNFAIP3, TNIP1, STAT3
 GO:0006954 45 / 467 4.6× 1.13e-17 1.24e-14 ✓ sig.
adaptive immune response
CAMK4, CARD9, CTLA4, CTSH, ERAP2, HLA-B, HLA-DMB, HLA-DOA, HLA-DPA1, HLA-DQB1, IL18RAP, JAK2
 GO:0002250 45 / 507 4.2× 2.57e-16 2.18e-13 ✓ sig.
peptide antigen assembly with MHC class II protein complex
HLA-DMB, HLA-DOA, HLA-DPA1, HLA-DQB1, B2M, HLA-DQA1, HLA-DRA, HLA-DRB1, HLA-DOB, HLA-DPB1, HLA-DQB2
 GO:0002503 11 / 16 32.8× 1.20e-15 8.86e-13 ✓ sig.
antigen processing and presentation of peptide or polysaccharide antigen via MHC class II
HLA-DMB, HLA-DOA, HLA-DPA1, HLA-DQB1, HLA-DQA1, HLA-DRA, HLA-DRB1, HLA-DOB, HLA-DPB1, HLA-DQB2
 GO:0002504 10 / 15 31.8× 4.03e-14 2.32e-11 ✓ sig.
cell surface receptor signaling pathway
ADGRL2, CBLB, CD28, FLT3, IL2RA, LRRK2, TICAM1, TNFRSF14, TNFSF15, CD274, CD40LG, CXCR3
 GO:0007166 35 / 373 4.5× 1.26e-13 6.71e-11 ✓ sig.
positive regulation of T cell activation
CCDC88B, CD28, HLA-DMB, HLA-DOA, HLA-DPA1, HLA-DQB1, B2M, HLA-DQA1, HLA-DRA, HLA-DRB1, CCR2, HLA-DOB
 GO:0050870 14 / 45 14.8× 2.35e-13 1.19e-10 ✓ sig.
antigen processing and presentation of exogenous peptide antigen via MHC class II
HLA-DMB, HLA-DOA, HLA-DPA1, HLA-DQB1, B2M, FCGR2B, HLA-DQA1, HLA-DRA, HLA-DRB1, HLA-DOB, HLA-DPB1, HLA-DQB2
 GO:0019886 12 / 31 18.5× 6.05e-13 2.82e-10 ✓ sig.
positive regulation of immune response
HLA-DMB, HLA-DOA, HLA-DPA1, HLA-DQB1, B2M, TGFB2, HLA-DQA1, HLA-DRA, HLA-DRB1, HLA-DOB, HLA-DPB1, HLA-DQB2
 GO:0050778 13 / 40 15.5× 9.01e-13 4.08e-10 ✓ sig.
antigen processing and presentation
CTSH, HLA-B, HLA-DMB, HLA-DOA, HLA-DPA1, HLA-DQB1, RAB5B, HLA-DQA1, HLA-DRA, HLA-DRB1, HLA-DOB, HLA-DPB1
 GO:0019882 13 / 48 12.9× 1.24e-11 4.40e-9 ✓ sig.
positive regulation of tumor necrosis factor production
CARD9, JAK2, LRRK2, TICAM1, STAT3, FCGR2B, IFNG, IL17A, IL6, PF4, IFIH1, TLR3
 GO:0032760 18 / 113 7.6× 2.29e-11 7.64e-9 ✓ sig.
cellular response to lipopolysaccharide
IL10, JAK2, TICAM1, TNFAIP3, TNIP1, CD274, AICDA, B2M, IL6, PF4, CD86, CX3CR1
 GO:0071222 22 / 187 5.6× 6.63e-11 1.96e-8 ✓ sig.
T cell receptor signaling pathway
CBLB, CD28, CTLA4, GATA3, HLA-DQB1, PTPN22, ZAP70, BTNL2, CD247, FYN, HLA-DRB1, CSK
 GO:0050852 18 / 121 7.1× 7.45e-11 2.17e-8 ✓ sig.

Pairs within this cluster, by significance

Disease A ⇵ Disease B ⇵ Similarity score ⇵ Shared genes ⇵ P-value ⇵ FDR q-value ⇵
Autoimmune disease Autoimmune thyroid disease 0.335 87 2.91e-133 4.71e-131 ✓ sig.
Autoimmune disease Celiac disease 0.249 79 6.05e-102 7.15e-100 ✓ sig.
Autoimmune thyroid disease Celiac disease 0.229 63 4.55e-84 3.84e-82 ✓ sig.
Autoimmune thyroid disease Common variable immunodeficiency 0.272 47 2.53e-79 1.99e-77 ✓ sig.
Autoimmune disease Common variable immunodeficiency 0.209 48 1.57e-73 1.17e-71 ✓ sig.
Celiac disease Common variable immunodeficiency 0.212 47 2.34e-72 1.73e-70 ✓ sig.
Common variable immunodeficiency immunodeficiency, common variable, 4 0.013 1 4.87e-3 5.99e-3 ✓ sig.
Common variable immunodeficiency immunodeficiency, common variable, 6 0.013 1 4.87e-3 5.99e-3 ✓ sig.
Common variable immunodeficiency immunodeficiency, common variable, 7 0.013 1 4.87e-3 5.99e-3 ✓ sig.
Common variable immunodeficiency isolated sulfite oxidase deficiency 0.013 1 4.87e-3 5.99e-3 ✓ sig.
Autoimmune thyroid disease isolated sulfite oxidase deficiency 0.007 1 9.35e-3 1.07e-2 ✓ sig.
Celiac disease isolated sulfite oxidase deficiency 0.005 1 1.25e-2 1.40e-2 ✓ sig.
Autoimmune disease Autoinflammation with pulmonary and cutaneous vasculitis 0.005 1 1.31e-2 1.46e-2 ✓ sig.