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

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Locus annotations

Locus 36

Top associations per target

Target cis/​trans Study SNP SNP location Maj/​min allele MAF N βinv seinv Pinv fclog Plog Praw
DC-SIGN trans Discovery rs505922 9:136,149,229 T/C 0.35 996 0.818 0.038 7.6×10-86 1.320 5.2×10-88 2.5×10-66
DC-SIGN trans Replication rs687289 9:136,137,106 G/A 0.40 337 0.718 0.059 4.1×10-28 1.310 2.1×10-25 2.1×10-6
vWF trans Discovery rs612169 9:136,143,442 A/G 0.35 996 0.417 0.044 1.2×10-20 1.150 2.9×10-19 5.5×10-18
vWF trans Replication rs657152 9:136,139,265 C/A 0.41 337 0.387 0.066 10×10-9 1.180 5×10-8 8.6×10-5
MBL trans Discovery rs687289 9:136,137,106 G/A 0.36 989 0.282 0.045 8.2×10-10 1.160 6.8×10-9 5.2×10-10
MBL trans Replication rs687289 9:136,137,106 G/A 0.40 337 0.171 0.072 0.019 1.090 0.078 0.004

 

Regional association plots

 

Boxplots and histograms for top associations

CD209 antigen (DC-SIGN)

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

von Willebrand factor (vWF)

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

Mannose-binding protein C (MBL)

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

CD209 antigen (DC-SIGN)

Target (abbrv.) DC-SIGN
Target (full name) CD209 antigen
Somalogic ID (Sequence ID) SL005157 (3029-52_2)
Entrez Gene Symbol CD209
UniProt ID Q9NNX6
UniProt Comment
  • Pathogen-recognition receptor expressed on the surface of immature dendritic cells (DCs) and involved in initiation of primary immune response. Thought to mediate the endocytosis of pathogens which are subsequently degraded in lysosomal compartments. The receptor returns to the cell membrane surface and the pathogen-derived antigens are presented to resting T-cells via MHC class II proteins to initiate the adaptive immune response.
Reactome
  • CD209 (DC-SIGN) signaling
Pathway Studio
  • DC-SIGN (CD209) Signaling

von Willebrand factor (vWF)

Target (abbrv.) vWF
Target (full name) von Willebrand factor
Somalogic ID (Sequence ID) SL000017 (3050-7_2)
Entrez Gene Symbol VWF
UniProt ID P04275
UniProt Comment
  • Important in the maintenance of hemostasis, it promotes adhesion of platelets to the sites of vascular injury by forming a molecular bridge between sub-endothelial collagen matrix and platelet-surface receptor complex GPIb-IX-V. Also acts as a chaperone for coagulation factor VIII, delivering it to the site of injury, stabilizing its heterodimeric structure and protecting it from premature clearance from plasma.
Biomarker applications (based on IPA annotation)
  • diagnosis
  • efficacy
  • prognosis
Wiki Pathways
  • Blood Clotting Cascade
  • Complement and Coagulation Cascades
  • Focal Adhesion
Reactome
  • GP1b-IX-V activation signalling
  • GRB2:SOS provides linkage to MAPK signaling for Integrins
  • Integrin alphaIIb beta3 signaling
  • Integrin cell surface interactions
  • Intrinsic Pathway of Fibrin Clot Formation
  • Platelet Adhesion to exposed collagen
  • Platelet degranulation
  • p130Cas linkage to MAPK signaling for integrins

Mannose-binding protein C (MBL)

Target (abbrv.) MBL
Target (full name) Mannose-binding protein C
Somalogic ID (Sequence ID) SL004516 (3000-66_1)
Entrez Gene Symbol MBL2
UniProt ID P11226
UniProt Comment
  • Calcium-dependent lectin involved in innate immune defense. Binds mannose, fucose and N-acetylglucosamine on different microorganisms and activates the lectin complement pathway. Binds to late apoptotic cells, as well as to apoptotic blebs and to necrotic cells, but not to early apoptotic cells, facilitating their uptake by macrophages. May bind DNA.
Biomarker applications (based on IPA annotation)
  • diagnosis
Wiki Pathways
  • Regulation of toll-like receptor signaling pathway
Reactome
  • Initial triggering of complement
  • Lectin pathway of complement activation
Pathway Studio
  • Lectin-Induced Complement Pathway

All locus annotations are based on the sentinel SNP (rs505922) and 34 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
  • ABO ABO blood group (transferase A, alpha 1-3-N-acetylgalactosaminyltransferase; transferase B, alpha 1-3-galactosyltransferase)
Potentially regulated genes
  • TSC1 tuberous sclerosis 1
  • TSC1
  • ABO ABO blood group (transferase A, alpha 1-3-N-acetylgalactosaminyltransferase; transferase B, alpha 1-3-galactosyltransferase)
  • AK8 adenylate kinase 8
  • ABO
  • SARDH sarcosine dehydrogenase
eQTL genes
  • ABO ABO blood group (transferase A, alpha 1-3-N-acetylgalactosaminyltransferase; transferase B, alpha 1-3-galactosyltransferase)
  • GBGT1 globoside alpha-1,3-N-acetylgalactosaminyltransferase 1

 

Results from other genome-wide association studies

Trait P Study Source
cg11879188 (chr9:136149884) 3.3×10-310 10.1101/033084 (DOI) BIOS QTL cis-meQTLs
cg21160290 (chr9:136149917) 3.3×10-310 10.1101/033084 (DOI) BIOS QTL cis-meQTLs
cg24267699 (chr9:136151383) 3.3×10-310 10.1101/033084 (DOI) BIOS QTL cis-meQTLs
ABO system O blood type 1×10-300 22611595 (PMID) GRASP2 nonQTL
von Willebrand factor (vWF) 9.7×10-223 21534939 (PMID) GRASP2 nonQTL
cg13531387 (chr9:136078681) 2.7×10-193 10.1101/033084 (DOI) BIOS QTL cis-meQTLs
Activated partial thromboplastin time 9×10-100 22703881 (PMID) GRASP2 nonQTL
cg00878953 (chr9:136129899) 2×10-80 10.1101/033084 (DOI) BIOS QTL cis-meQTLs
Blood soluble E-selectin levels (female) 1×10-57 20147318 (PMID) GRASP2 nonQTL
Venous thromboembolism 1.6×10-52 23650146 (PMID) GRASP2 nonQTL
Soluble intercellular adhesion molecule 1 (ICAM-1) 1.6×10-52 21533024 (PMID) GRASP2 nonQTL
Metabolic syndrome domains (Multivariate analysis) 9.7×10-48 22022282 (PMID) GRASP2 nonQTL
Circulating galectin-3 levels 3.7×10-47 23056639 (PMID) GRASP2 nonQTL
TNF-alpha (TNF-a), pg/ml 2.6×10-43 18464913 (PMID) GRASP2 nonQTL
TNF-alpha (TNF-a) 6.8×10-40 18464913 (PMID) GRASP2 nonQTL
Serum ratio of (ADpSGEGDFXAEGGGVR)/(ADSGEGDFXAEGGGVR) 9.1×10-40 21886157 (PMID) GRASP2 metabQTL
Serum ratio of (ADpSGEGDFXAEGGGVR*)/(ADSGEGDFXAEGGGVR*) 9.1×10-40 21886157 (PMID) GRASP2 metabQTL
Alkaline phosphatase (ALP) 1.4×10-38 20139978 (PMID) GRASP2 nonQTL
cg18089000 (chr9:136039682) 7.4×10-37 10.1101/033084 (DOI) BIOS QTL cis-meQTLs
Factor XIII antigen 1.2×10-36 23381943 (PMID) GRASP2 nonQTL
Venous thrombosis 5×10-35 22675575 (PMID) GRASP2 nonQTL
cg03474926 (chr9:136023383) 1.1×10-33 10.1101/033084 (DOI) BIOS QTL cis-meQTLs
Serum ratio of (ADpSGEGDFXAEGGGVR*)/(DSGEGDFXAEGGGVR*) 2×10-33 21886157 (PMID) GRASP2 metabQTL
Interleukin-6 (IL-6) levels 2.1×10-29 22291609 (PMID) GRASP2 nonQTL
Triglycerides 2.1×10-26 24097068 (PMID) Supplemental file
cg14653977 (chr9:136038716) 6.4×10-25 10.1101/033084 (DOI) BIOS QTL cis-meQTLs
LDL cholesterol 1.3×10-24 24097068 (PMID) Supplemental file
Serum soluble E-selectin 1.9×10-19 19729612 (PMID) GRASP2 nonQTL
Blood soluble E-selectin levels (in non-diabetic females) 1.6×10-17 20147318 (PMID) GRASP2 nonQTL
Plasma soluble intercellular adhesion molecule 1 (ICAM-1) (females) 9.2×10-17 18604267 (PMID) GRASP2 nonQTL
Blood soluble E-selectin levels (in diabetic females) 1.5×10-15 20147318 (PMID) GRASP2 nonQTL
cg04703696 (chr9:136036605) 3×10-15 10.1101/033084 (DOI) BIOS QTL cis-meQTLs
Venous thromboembolism (VTE) 3.7×10-15 19278955 (PMID) GRASP2 nonQTL
Total cholesterol 3.9×10-15 20686565 (PMID) GRASP2 nonQTL
cg13568213 (chr9:136387259) 2.9×10-14 10.1101/033084 (DOI) BIOS QTL cis-meQTLs
Serum concentration of ADpSGEGDFXAEGGGVR* 3.8×10-14 21886157 (PMID) GRASP2 metabQTL
Thyroid stimulating hormone (TSH) 5×10-14 23408906 (PMID) GRASP2 nonQTL
Gene expression of ABO (probeID ILMN_1656979) in temporal cortex in Alzheimer's disease cases and controls 6×10-14 22685416 (PMID) GRASP2 eQTL
ADpSGEGDFXAEGGGVR* 9.7×10-14 24816252 (PMID) gwas.eu via SNiPA
Gastric parietal cell antibody positive (PCA) Type 1 diabetes 1.2×10-13 21829393 (PMID) GRASP2 nonQTL
Gene expression of ABO (probeID ILMN_1656979) in cerebellum in Alzheimer's disease cases and controls 2.2×10-13 22685416 (PMID) GRASP2 eQTL
Gene expression of ABO in normal prepouch ileum 8.5×10-13 23474282 (PMID) GRASP2 eQTL
Serum phytosterol (campesterol) 9.4×10-13 20529992 (PMID) GRASP2 nonQTL
cg13892928 (chr9:136072382) 7.5×10-11 10.1101/033084 (DOI) BIOS QTL cis-meQTLs
Duodenal ulcer 1.2×10-10 22387998 (PMID) GRASP2 nonQTL
Serum phytosterol (campesterol normalized to cholesterol) 2.2×10-10 20529992 (PMID) GRASP2 nonQTL
Graves' disease 2.5×10-10 23612905 (PMID) GRASP2 nonQTL
Serum phytosterol 2.8×10-10 20529992 (PMID) GRASP2 nonQTL
Gene expression of ABO (probeID ILMN_1656979) in cerebellum in non-Alzheimer's disease samples 3.1×10-10 22685416 (PMID) GRASP2 eQTL
Serum metabolite (mass spec peak: 512.2 m/z) 4×10-10 23281178 (PMID) GRASP2 metabQTL
Serum concentration of ADSGEGDFXAEGGGVR* 9.5×10-10 21886157 (PMID) GRASP2 metabQTL
Serum phytosterol normalized to cholesterol 3.5×10-9 20529992 (PMID) GRASP2 nonQTL
Insulin processing and secretion 3.8×10-9 23263489 (PMID) GRASP2 nonQTL
Myocardial infarction (MI) in patients with coronary artery disease (CAD) by angiography 7.6×10-9 21239051 (PMID) GRASP2 nonQTL
Fasting serum interleukin-6 (IL-6) (pg/mL) in children 2×10-8 23251661 (PMID) GRASP2 nonQTL
Malaria 2.3×10-8 23717212 (PMID) GRASP2 nonQTL
Serum phytosterol (sitosterol) 2.4×10-8 20529992 (PMID) GRASP2 nonQTL
Pancreatic cancer 2.6×10-8 19648918 (PMID) GRASP2 nonQTL
Serum metabolite (mass spec peak: 765.4 m/z) 6×10-8 23281178 (PMID) GRASP2 metabQTL
Gene expression of ABO (probeID ILMN_1656979) in temporal cortex in non-Alzheimer's disease samples 7.4×10-8 22685416 (PMID) GRASP2 eQTL
cg14600041 (chr9:136081555) 1.4×10-7 10.1101/033084 (DOI) BIOS QTL cis-meQTLs
Red blood cell count (RBC) 3.7×10-7 23222517 (PMID) GRASP2 nonQTL
Gene expression of ABO (probeID ILMN_1656979) in temporal cortex in Alzheimer's disease cases 4×10-7 22685416 (PMID) GRASP2 eQTL
Serum phytosterol (brassicasterol) 4.9×10-7 20529992 (PMID) GRASP2 nonQTL
Serum phytosterol (sitosterol normalized to cholesterol) 5.1×10-7 20529992 (PMID) GRASP2 nonQTL
Hematocrit (Hct) 7×10-7 23222517 (PMID) GRASP2 nonQTL
Thyroid stimulating hormone (TSH) (males) 1×10-6 23408906 (PMID) GRASP2 nonQTL
Coronary artery disease (CAD) 4.2×10-6 22319020 (PMID) GRASP2 nonQTL
Grave's disease 6.4×10-6 21841780 (PMID) GRASP2 nonQTL
Plasma fibrin D-dimer levels 7×10-6 21502573 (PMID) GRASP2 nonQTL
cg14802951 (chr9:136287433) 9.4×10-6 10.1101/033084 (DOI) BIOS QTL cis-meQTLs
Thyroid stimulating hormone (TSH) (females) 1.3×10-5 23408906 (PMID) GRASP2 nonQTL
Gene expression of ABO (probeID ILMN_1656979) in cerebellum in Progressive Supranuclear Palsy cases 1.4×10-5 22685416 (PMID) GRASP2 eQTL
Gene expression of ABO (probeID ILMN_1656979) in temporal cortex in Progressive Supranuclear Palsy cases 1.5×10-5 22685416 (PMID) GRASP2 eQTL
2h glucose 2.3×10-5 22885924 (PMID) Supplemental file
Gene expression of ABO in CD4+ lymphocytes 2.7×10-5 20833654 (PMID) GRASP2 eQTL
Gene expression of ABO (probeID ILMN_1656979) in cerebellum in Alzheimer's disease cases 3×10-5 22685416 (PMID) GRASP2 eQTL
Alcohol behavior (binary alcohol dependence diagnosis) 4.1×10-5 21529783 (PMID) GRASP2 nonQTL
Serum phytosterol (brassicasterol normalized to cholesterol) 5×10-5 20529992 (PMID) GRASP2 nonQTL
cg14416294 (chr9:136362298) 6.2×10-5 10.1101/033084 (DOI) BIOS QTL cis-meQTLs
Essential hypertension 6.3×10-5 22184326 (PMID) GRASP2 nonQTL
Digit Span Forward 1×10-4 20125193 (PMID) GRASP2 nonQTL
Coronary artery disease and myocardial infarction 1.1×10-4 23202125 (PMID) Supplemental file
Adiponectin levels 2×10-4 22479202 (PMID) GRASP2 nonQTL
Cardioembolic stroke 2×10-4 23381943 (PMID) GRASP2 nonQTL
HDL cholesterol 2.8×10-4 24097068 (PMID) Supplemental file
Type 2 diabetes 3.5×10-4 22158537 (PMID) GRASP2 nonQTL
Metabolic syndrome domains (Atherogenic Dyslipidemia - PC1) 4.9×10-4 22022282 (PMID) GRASP2 nonQTL

The pleiotropic ABO locus is discussed in the main paper.

This locus is discussed in the main paper. Here we report observations not mentioned in the paper: In Shin et al. [PubMed] SNP rs651007 associates with dipeptide levels (aspartylphenylalanine, p=2×10-7; X-14189, annotated as potential Leu-Ala, but Ser-Pro is also possible by mass alone, p=9.6×10-10; X14304, I/L-Ala or Ala-I/L?, p=1.8×10-8; X-14208, could be Cys-Met or Tyr-Ala or His-Pro or Ser-Phe by mass alone, p=1.5×10-7; X-14205; X14086: annotated as Thr-Glu, but mass is 25 too high; Val-Arg possible by mass alone). This SNP also associates in Raffler et al. [PubMed] (Urine NMR) with a signal at 2.0308 ppm (PM20308, p=5.1×10-20). It is also a marginal hit in CardioGram (7.1×10-8). He et al. [PubMed] report a genome wide association study of genetic loci that influence tumour biomarkers cancer antigen 19-9, carcinoembryonic antigen and α fetoprotein and their associations with cancer risk. The authors find strong association of SNP rs8176749 with carcinoembryonic antigen (CEA) levels – we find association with Cadherin-5. CD209 and MBL2 are both lectins. All associated ABO-associated proteins are glycoproteins, part of glycoprotein complex (LY96), or glycoprotein-binding (SELE), except for IL27RA (http://jcggdb.jp/rcmg/gpdb/index). According to Uniprot all proteins are glycoproteins (including associations non-replicated in QMDiab), while only half of all SomaLogic proteins are glycoproteins. The Panther classification system (http://pantherdb.org/tools/compareToRefList.jsp) reported a significant enrichment of the GO process "endothelial cell differentiation" (GO:0045446): 5 out of 17 annotated proteins were found (expected were 0.32, p=1.45×10-5).



Subnetwork of the ABO locus.Six replicated pQTLs at the ABO gene locus (red), including SNP identifiers that are linked to the the six loci (light green KORA SNPs, yellow QMDiab SNPs, bright green both), pQTLS (blue), proteins with significant partial correlation are connected, associations with GWAS endpoints are shown (grey) [NOTE: the anorexia is a false positive, checked this with the consortium].

The information gathered here is a result of an attempt to keep track of all interesting information that we encountered while investigating these loci. Please bear in mind that the annotation given here is neither complete nor free of errors, and that all information provided here should be confirmed by additional literature research before being used as a basis for firm conclusions or further experiments.