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Connecting genetic risk to disease endpoints through the human blood plasma proteome

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Locus annotations

Locus 372

Top associations per target

Target cis/​trans Study SNP SNP location Maj/​min allele MAF N βinv seinv Pinv fclog Plog Praw
C4 cis Discovery rs2239805 6:32,411,376 T/G 0.17 997 -0.408 0.057 1.4×10-12 -1.080 3.5×10-11 4.2×10-12
C4 cis Replication rs1980493 6:32,363,215 A/G 0.05 337 0.056 0.174 0.746 -1.020 0.681 0.796

 

Regional association plots

 

Boxplots and histograms for top associations

Complement C4 (C4)

inverse-normalized probe levels log2 transformed probe levels raw probe levels
Discovery study
Replication study

Complement C4 (C4)

Target (abbrv.) C4
Target (full name) Complement C4
Somalogic ID (Sequence ID) SL000316 (4481-34_2)
Entrez Gene Symbol C4A, C4B
UniProt ID P0C0L4, P0C0L5
UniProt Comment
  • P0C0L4: Non-enzymatic component of C3 and C5 convertases and thus essential for the propagation of the classical complement pathway. Covalently binds to immunoglobulins and immune complexes and enhances the solubilization of immune aggregates and the clearance of IC through CR1 on erythrocytes. C4A isotype is responsible for effective binding to form amide bonds with immune aggregates or protein antigens, while C4B isotype catalyzes the transacylation of the thioester carbonyl group to form ester bonds with carbohydrate antigens.
  • P0C0L5: Non-enzymatic component of the C3 and C5 convertases and thus essential for the propagation of the classical complement pathway. Covalently binds to immunoglobulins and immune complexes and enhances the solubilization of immune aggregates and the clearance of IC through CR1 on erythrocytes. C4A isotype is responsible for effective binding to form amide bonds with immune aggregates or protein antigens, while C4B isotype catalyzes the transacylation of the thioester carbonyl group to form ester bonds with carbohydrate antigens.
Wiki Pathways
  • Complement Activation, Classical Pathway
  • SIDS Susceptibility Pathways
Reactome
  • Activation of C3 and C5
  • Initial triggering of complement
  • Regulation of Complement cascade

All locus annotations are based on the sentinel SNP (rs2239805) and 78 proxy variant(s) that is/are in linkage disequilibrium r2 ≥ 0.8. Linkage disequilibrium is based on data from the 1000 Genomes Project, phase 3 version 5, European population and was retrieved using SNiPA's Block Annotation feature.
Download the detailed results of SNiPA's block annotation (PDF)

Linked genes

Genes hit or close-by
  • HLA-DRA major histocompatibility complex, class II, DR alpha
  • HLA-DRB9 major histocompatibility complex, class II, DR beta 9 (pseudogene)
Potentially regulated genes
eQTL genes
  • C4A complement component 4A (Rodgers blood group)
  • HLA-DRB5 major histocompatibility complex, class II, DR beta 5
  • RNF5 ring finger protein 5, E3 ubiquitin protein ligase
  • HLA-DRB6 major histocompatibility complex, class II, DR beta 6 (pseudogene)
  • NOTCH4 notch 4
  • HLA-DRB1 major histocompatibility complex, class II, DR beta 1
  • HLA-DMA major histocompatibility complex, class II, DM alpha
  • C4B complement component 4B (Chido blood group)
  • PSMB9 proteasome (prosome, macropain) subunit, beta type, 9
  • CYP21A2 cytochrome P450, family 21, subfamily A, polypeptide 2
  • HLA-DPB1 major histocompatibility complex, class II, DP beta 1
  • CYP21A1P cytochrome P450, family 21, subfamily A, polypeptide 1 pseudogene
  • MICB MHC class I polypeptide-related sequence B
  • C6orf25 chromosome 6 open reading frame 25
  • LY6G6C lymphocyte antigen 6 complex, locus G6C
  • XXbac-BPG300A18.13
  • TNXA tenascin XA (pseudogene)
  • HLA-DQA2 major histocompatibility complex, class II, DQ alpha 2
  • XXbac-BPG246D15.9
  • HLA-DOB major histocompatibility complex, class II, DO beta
  • LIMS1 LIM and senescent cell antigen-like domains 1
  • HLA-DRA major histocompatibility complex, class II, DR alpha
  • HLA-DMB major histocompatibility complex, class II, DM beta
  • LST1 leukocyte specific transcript 1
  • HLA-DRB9 major histocompatibility complex, class II, DR beta 9 (pseudogene)
  • HCP5 HLA complex P5 (non-protein coding)
  • APOM apolipoprotein M

 

Results from other genome-wide association studies

Trait P Study Source
cg25645491 (chr6:32411091) 3.3×10-310 10.1101/033084 (DOI) BIOS QTL cis-meQTLs
Gene expression of HLA-DRB5 (probeID ILMN_1701686) in whole blood 5.4×10-80 22692066 (PMID) GRASP2 eQTL
Myasthenia gravis 3.9×10-73 23055271 (PMID) GRASP2 nonQTL
Rheumatoid arthritis 3.5×10-68 20453842 (PMID) GRASP2 nonQTL
Type 1 diabetes, combined control dataset 8×10-60 17554300 (PMID) GRASP2 nonQTL
Gene expression of HLA-DRB5///HLA-DRB1 in blood 2.4×10-58 21829388 (PMID) GRASP2 eQTL
Gene expression of HLA-DRB1 in peripheral blood monocytes 2.1×10-52 20502693 (PMID) GRASP2 eQTL
Gene expression of HLA-DRB4 in peripheral blood monocytes 9.2×10-42 20502693 (PMID) GRASP2 eQTL
Gene expression of HLA-DRB6 in peripheral blood monocytes 1.3×10-30 20502693 (PMID) GRASP2 eQTL
Rheumatoid arthritis (ACPA-positive) 2.7×10-29 21156761 (PMID) GRASP2 nonQTL
Idiopathic membranous nephropathy 1.2×10-22 21323541 (PMID) GRASP2 nonQTL
Gene expression of HLA-DRB1 [probe 221491_x_at] in lymphoblastoid cell lines 1.8×10-21 17873877 (PMID) GRASP2 eQTL
Gene expression of HLA-DRB2 [probe 221491_x_at] in lymphoblastoid cell lines 1.8×10-21 17873877 (PMID) GRASP2 eQTL
Gene expression of HLA-DRB3 [probe 221491_x_at] in lymphoblastoid cell lines 1.8×10-21 17873877 (PMID) GRASP2 eQTL
Gene expression of HLA-DRB4 [probe 221491_x_at] in lymphoblastoid cell lines 1.8×10-21 17873877 (PMID) GRASP2 eQTL
Gene expression of HLA-DRB5 [probe 221491_x_at] in lymphoblastoid cell lines 1.8×10-21 17873877 (PMID) GRASP2 eQTL
Gene expression of LOC100133484 [probe 221491_x_at] in lymphoblastoid cell lines 1.8×10-21 17873877 (PMID) GRASP2 eQTL
Gene expression of LOC100133661 [probe 221491_x_at] in lymphoblastoid cell lines 1.8×10-21 17873877 (PMID) GRASP2 eQTL
Gene expression of LOC100133811 [probe 221491_x_at] in lymphoblastoid cell lines 1.8×10-21 17873877 (PMID) GRASP2 eQTL
Gene expression of LOC730415 [probe 221491_x_at] in lymphoblastoid cell lines 1.8×10-21 17873877 (PMID) GRASP2 eQTL
Gene expression of LOC731718 [probe 221491_x_at] in lymphoblastoid cell lines 1.8×10-21 17873877 (PMID) GRASP2 eQTL
Gene expression of RNASE2 [probe 221491_x_at] in lymphoblastoid cell lines 1.8×10-21 17873877 (PMID) GRASP2 eQTL
Gene expression of ZNF749 [probe 221491_x_at] in lymphoblastoid cell lines 1.8×10-21 17873877 (PMID) GRASP2 eQTL
Alopecia areata 2.2×10-19 20596022 (PMID) GRASP2 nonQTL
Gene expression of HLA-DRB1 [probe 204670_x_at] in lymphoblastoid cell lines 8.8×10-18 17873877 (PMID) GRASP2 eQTL
Gene expression of HLA-DRB2 [probe 204670_x_at] in lymphoblastoid cell lines 8.8×10-18 17873877 (PMID) GRASP2 eQTL
Gene expression of HLA-DRB3 [probe 204670_x_at] in lymphoblastoid cell lines 8.8×10-18 17873877 (PMID) GRASP2 eQTL
Gene expression of HLA-DRB4 [probe 204670_x_at] in lymphoblastoid cell lines 8.8×10-18 17873877 (PMID) GRASP2 eQTL
Gene expression of HLA-DRB5 [probe 204670_x_at] in lymphoblastoid cell lines 8.8×10-18 17873877 (PMID) GRASP2 eQTL
Gene expression of LOC100133484 [probe 204670_x_at] in lymphoblastoid cell lines 8.8×10-18 17873877 (PMID) GRASP2 eQTL
Gene expression of LOC100133661 [probe 204670_x_at] in lymphoblastoid cell lines 8.8×10-18 17873877 (PMID) GRASP2 eQTL
Gene expression of LOC100133811 [probe 204670_x_at] in lymphoblastoid cell lines 8.8×10-18 17873877 (PMID) GRASP2 eQTL
Gene expression of LOC730415 [probe 204670_x_at] in lymphoblastoid cell lines 8.8×10-18 17873877 (PMID) GRASP2 eQTL
Gene expression of RNASE2 [probe 204670_x_at] in lymphoblastoid cell lines 8.8×10-18 17873877 (PMID) GRASP2 eQTL
Gene expression of ZNF749 [probe 204670_x_at] in lymphoblastoid cell lines 8.8×10-18 17873877 (PMID) GRASP2 eQTL
Schizophrenia 4.1×10-17 25056061 (PMID) Supplemental file
Type 1 diabetes 1×10-16 17632545 (PMID) GRASP2 nonQTL
cg25457674 (chr6:32303796) 2×10-16 10.1101/033084 (DOI) BIOS QTL cis-meQTLs
Gene expression of HLA-DRB5 in peripheral blood monocytes 2.6×10-16 20502693 (PMID) GRASP2 eQTL
cg16072814 (chr6:32189421) 3.1×10-16 10.1101/033084 (DOI) BIOS QTL cis-meQTLs
Gene expression of HLA-DPB1 in peripheral blood monocytes 3.8×10-16 20502693 (PMID) GRASP2 eQTL
Gene expression of HLA-DRA (probeID ILMN_2157441) in cerebellum in Alzheimer's disease cases and controls 5.8×10-16 22685416 (PMID) GRASP2 eQTL
Gene expression of HLA-DRA (probeID ILMN_2157441) in temporal cortex in Alzheimer's disease cases and controls 1.1×10-14 22685416 (PMID) GRASP2 eQTL
Lupus erythematosus, systemic 3.2×10-14 pha002848 (dbGaP) dbGaP via SNiPA
cg06968241 (chr6:32411120) 1×10-13 10.1101/033084 (DOI) BIOS QTL cis-meQTLs
Gene expression of HLA-DRB4 [probe 209728_at] in lymphoblastoid cell lines 1.5×10-13 17873877 (PMID) GRASP2 eQTL
Gene expression of HLA-DRB1 in lymphoblastoid cell lines 1.6×10-13 17873877 (PMID) GRASP2 eQTL
Gene expression of HLA-DQA1 [probe 203290_at] in lymphoblastoid cell lines 1.4×10-12 17873877 (PMID) GRASP2 eQTL
Gene expression of HLA-DOB in peripheral blood monocytes 2.1×10-12 20502693 (PMID) GRASP2 eQTL
cg10254167 (chr6:32374980) 3.9×10-11 10.1101/033084 (DOI) BIOS QTL cis-meQTLs
Gene expression of HLA-DRB5 in CEU-CHB-JPT lymphoblastoid cell lines 1.3×10-10 17873874 (PMID) GRASP2 eQTL
Gene expression levels of HLA-DRB5 in muscle 4×10-10 21299892 (PMID) GRASP2 eQTL
cg15706017 (chr6:32269135) 5.6×10-10 10.1101/033084 (DOI) BIOS QTL cis-meQTLs
Gene expression of HLA-DRB4 in lymphoblastoid cell lines 6.6×10-10 17873877 (PMID) GRASP2 eQTL
Gene expression of HLA-DRB1 [probe 209312_x_at] in lymphoblastoid cell lines 6.6×10-10 17873877 (PMID) GRASP2 eQTL
Gene expression of HLA-DRB2 [probe 209312_x_at] in lymphoblastoid cell lines 6.6×10-10 17873877 (PMID) GRASP2 eQTL
Gene expression of HLA-DRB3 [probe 209312_x_at] in lymphoblastoid cell lines 6.6×10-10 17873877 (PMID) GRASP2 eQTL
Gene expression of HLA-DRB4 [probe 209312_x_at] in lymphoblastoid cell lines 6.6×10-10 17873877 (PMID) GRASP2 eQTL
Gene expression of HLA-DRB5 [probe 209312_x_at] in lymphoblastoid cell lines 6.6×10-10 17873877 (PMID) GRASP2 eQTL
Gene expression of LOC100133484 [probe 209312_x_at] in lymphoblastoid cell lines 6.6×10-10 17873877 (PMID) GRASP2 eQTL
Gene expression of LOC100133661 [probe 209312_x_at] in lymphoblastoid cell lines 6.6×10-10 17873877 (PMID) GRASP2 eQTL
Gene expression of LOC100133811 [probe 209312_x_at] in lymphoblastoid cell lines 6.6×10-10 17873877 (PMID) GRASP2 eQTL
Gene expression of LOC730415 [probe 209312_x_at] in lymphoblastoid cell lines 6.6×10-10 17873877 (PMID) GRASP2 eQTL
Gene expression of RNASE2 [probe 209312_x_at] in lymphoblastoid cell lines 6.6×10-10 17873877 (PMID) GRASP2 eQTL
Gene expression of ZNF749 [probe 209312_x_at] in lymphoblastoid cell lines 6.6×10-10 17873877 (PMID) GRASP2 eQTL
HDL cholesterol 2.4×10-9 24097068 (PMID) Supplemental file
Gene expression of BTN3A2 in peripheral blood monocytes 2.6×10-9 20502693 (PMID) GRASP2 eQTL
Gene expression of LOC401118 in CHB-JPT lymphoblastoid cell lines 3.3×10-9 17873874 (PMID) GRASP2 eQTL
Gene expression of HLA-DRA in peripheral blood monocytes 3.7×10-9 20502693 (PMID) GRASP2 eQTL
Gene expression of HLA-DRB4 [probe 215666_at] in lymphoblastoid cell lines 4.1×10-9 17873877 (PMID) GRASP2 eQTL
Methylation levels at chr6:32515217-32515267 [hg18 coord, probe cg25764570] in Frontal cortex 4.3×10-9 20485568 (PMID) GRASP2 meQTL
Gene expression of PSMB9 in peripheral blood monocytes 4.6×10-9 20502693 (PMID) GRASP2 eQTL
Primary biliary cirrhosis 6.3×10-9 23000144 (PMID) GRASP2 nonQTL
Gene expression of HLA-DRA (probeID ILMN_2157441) in cerebellum in Alzheimer's disease cases 7.2×10-9 22685416 (PMID) GRASP2 eQTL
Gene expression of HLA-DQA1 in peripheral blood monocytes 2.5×10-8 20502693 (PMID) GRASP2 eQTL
Gene expression of HLA-DRB2 in blood cells in Celiac disease 4×10-8 19128478 (PMID) GRASP2 eQTL
Gene expression of HLA-DRA (probeID ILMN_2157441) in cerebellum in non-Alzheimer's disease samples 4.7×10-8 22685416 (PMID) GRASP2 eQTL
Height 7.4×10-8 25282103 (PMID) Supplemental file
Gene expression of HLA-DRB3 in peripheral blood monocytes 9.4×10-8 20502693 (PMID) GRASP2 eQTL
Gene expression of HLA-DRA (probeID ILMN_2157441) in temporal cortex in Alzheimer's disease cases 9.6×10-8 22685416 (PMID) GRASP2 eQTL
Gene expression of HLA-DQB1 in lymphoblastoid cell lines 1.8×10-7 17873877 (PMID) GRASP2 eQTL
Gene expression of IER3 in peripheral blood monocytes 2.9×10-7 20502693 (PMID) GRASP2 eQTL
Gene expression of HLA-DRA (probeID ILMN_2157441) in temporal cortex in non-Alzheimer's disease samples 3.1×10-7 22685416 (PMID) GRASP2 eQTL
Anti-cyclic citrullinated peptide titer 3.9×10-7 19287509 (PMID) GRASP2 nonQTL
Gene expression of ERG in peripheral blood monocytes 9.6×10-7 20502693 (PMID) GRASP2 eQTL
Cardiac neonatal lupus 1.5×10-6 20662065 (PMID) GRASP2 nonQTL
Gene expression of TRIM56 in peripheral blood monocytes 2.2×10-6 20502693 (PMID) GRASP2 eQTL
cg20671150 (chr6:32172127) 2.7×10-6 10.1101/033084 (DOI) BIOS QTL cis-meQTLs
Cross-disorder, subset Schizophrenia 4.6×10-6 23453885 (PMID) Supplemental file
Gene expression of [probe 1190754 centered at chr6:32731975] in blood 5.2×10-6 21829388 (PMID) GRASP2 eQTL
Triglycerides 8.7×10-6 24097068 (PMID) Supplemental file
Gene expression of C4B in liver 1.5×10-5 18462017 (PMID) GRASP2 eQTL
Waist-to-hip ratio, adjusted for BMI 1.7×10-5 25673412 (PMID) Supplemental file
Gene expression of C4A in liver 1.9×10-5 18462017 (PMID) GRASP2 eQTL
Spine bone mineral density (BMD) 2.3×10-5 18445777 (PMID) GRASP2 nonQTL
cg09441568 (chr6:32131017) 3.1×10-5 10.1101/033084 (DOI) BIOS QTL cis-meQTLs
Smoking behaviour, Former smoker 5.3×10-5 20418890 (PMID) Supplemental file
Gene expression of HSPA1B in normal prepouch ileum 5.9×10-5 23474282 (PMID) GRASP2 eQTL
Waist-to-hip ratio 8.7×10-5 25673412 (PMID) Supplemental file
cg19256906 (chr6:32187443) 1.2×10-4 10.1101/033084 (DOI) BIOS QTL cis-meQTLs
Advanced age-related macular degeneration (choroidal neovascularization) vs. no AMD 1.3×10-4 23455636 (PMID) GRASP2 nonQTL
Gene expression of RNF5///AGER in blood 1.4×10-4 21829388 (PMID) GRASP2 eQTL
Bipolar disorder vs. Schizophrenia 2.2×10-4 24280982 (PMID) Supplemental file
Total cholesterol 2.9×10-4 20686565 (PMID) GRASP2 nonQTL
Inflammatory bowel disease 3.7×10-4 Supplemental file
Breast cancer early age of onset 4×10-4 18463975 (PMID) GRASP2 nonQTL
Gene expression of HLA-DRA (probeID ILMN_2157441) in cerebellum in Progressive Supranuclear Palsy cases 4.2×10-4 22685416 (PMID) GRASP2 eQTL
Waist hip ratio 4.3×10-4 20935629 (PMID) GRASP2 nonQTL