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

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Locus annotations

Locus 354

Top associations per target

Target cis/​trans Study SNP SNP location Maj/​min allele MAF N βinv seinv Pinv fclog Plog Praw
sE-Selectin trans Discovery rs8176720 9:136,132,873 T/C 0.34 997 0.313 0.043 5.8×10-13 1.120 6×10-14 7.9×10-12
sE-Selectin trans Replication rs12554580 9:136,128,603 A/G 0.41 337 0.224 0.072 0.002 1.100 0.002 0.012
ATS13 cis Discovery rs8176720 9:136,132,873 T/C 0.34 997 -0.277 0.044 6.4×10-10 -1.060 2.3×10-10 2×10-9
ATS13 cis Replication rs12554580 9:136,128,603 A/G 0.41 337 -0.097 0.066 0.139 -1.030 0.099 0.147
IR trans Discovery rs8176720 9:136,132,873 T/C 0.34 997 0.280 0.045 7.4×10-10 1.070 9.7×10-9 7.8×10-6
IR trans Replication rs12554580 9:136,128,603 A/G 0.41 337 0.323 0.058 6.8×10-8 1.120 5.1×10-8 5.2×10-6

 

Regional association plots

E-Selectin (sE-Selectin)

Download the association data used to generate this plot

A disintegrin and metalloproteinase with thrombospondin motifs 13 (ATS13)

Download the association data used to generate this plot

Insulin receptor (IR)

Download the association data used to generate this plot

 

Boxplots and histograms for top associations

E-Selectin (sE-Selectin)

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

A disintegrin and metalloproteinase with thrombospondin motifs 13 (ATS13)

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

Insulin receptor (IR)

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

E-Selectin (sE-Selectin)

Target (abbrv.) sE-Selectin
Target (full name) E-Selectin
Somalogic ID (Sequence ID) SL001945 (3470-1_2)
Entrez Gene Symbol SELE
UniProt ID P16581
UniProt Comment
  • Cell-surface glycoprotein having a role in immunoadhesion. Mediates in the adhesion of blood neutrophils in cytokine-activated endothelium through interaction with PSGL1/SELPLG. May have a role in capillary morphogenesis.
Biomarker applications (based on IPA annotation)
  • diagnosis
  • disease progression
  • efficacy
  • unspecified application
Pathway Interaction Database
  • ATF-2 transcription factor network
  • Glucocorticoid receptor regulatory network
  • Thromboxane A2 receptor signaling
Reactome
  • Cell surface interactions at the vascular wall
Pathway Studio
  • Leukocyte Adhesion to Endothelial Cell
  • SELE → ELK-SRF signaling

A disintegrin and metalloproteinase with thrombospondin motifs 13 (ATS13)

Target (abbrv.) ATS13
Target (full name) A disintegrin and metalloproteinase with thrombospondin motifs 13
Somalogic ID (Sequence ID) SL006610 (3175-51_5)
Entrez Gene Symbol ADAMTS13
UniProt ID Q76LX8
UniProt Comment
  • Cleaves the vWF multimers in plasma into smaller forms thereby controlling vWF-mediated platelet thrombus formation.
Reactome
  • O-glycosylation of TSR domain-containing proteins

Insulin receptor (IR)

Target (abbrv.) IR
Target (full name) Insulin receptor
Somalogic ID (Sequence ID) SL004125 (3448-13_2)
Entrez Gene Symbol INSR
UniProt ID P06213
UniProt Comment
  • Receptor tyrosine kinase which mediates the pleiotropic actions of insulin. Binding of insulin leads to phosphorylation of several intracellular substrates, including, insulin receptor substrates (IRS1, 2, 3, 4), SHC, GAB1, CBL and other signaling intermediates. Each of these phosphorylated proteins serve as docking proteins for other signaling proteins that contain Src-homology-2 domains (SH2 domain) that specifically recognize different phosphotyrosines residues, including the p85 regulatory subunit of PI3K and SHP2. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway, which is responsible for most of the metabolic actions of insulin, and the Ras-MAPK pathway, which regulates expression of some genes and cooperates with the PI3K pathway to control cell growth and differentiation. Binding of the SH2 domains of PI3K to phosphotyrosines on IRS1 leads to the activation of PI3K and the generation of phosphatidylinositol-(3, 4, 5)-triphosphate (PIP3), a lipid second messenger, which activates several PIP3-dependent serine/threonine kinases, such as PDPK1 and subsequently AKT/PKB. The net effect of this pathway is to produce a translocation of the glucose transporter SLC2A4/GLUT4 from cytoplasmic vesicles to the cell membrane to facilitate glucose transport. Moreover, upon insulin stimulation, activated AKT/PKB is responsible for: anti-apoptotic effect of insulin by inducing phosphorylation of BAD; regulates the expression of gluconeogenic and lipogenic enzymes by controlling the activity of the winged helix or forkhead (FOX) class of transcription factors. Another pathway regulated by PI3K-AKT/PKB activation is mTORC1 signaling pathway which regulates cell growth and metabolism and integrates signals from insulin. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 thereby activating mTORC1 pathway. The Ras/RAF/MAP2K/MAPK pathway is mainly involved in mediating cell growth, survival and cellular differentiation of insulin. Phosphorylated IRS1 recruits GRB2/SOS complex, which triggers the activation of the Ras/RAF/MAP2K/MAPK pathway. In addition to binding insulin, the insulin receptor can bind insulin-like growth factors (IGFI and IGFII). Isoform Short has a higher affinity for IGFII binding. When present in a hybrid receptor with IGF1R, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin.
Targeted by drugs (based on IPA annotation)
  • insulin detemir
  • INS
  • canakinumab/INS
  • insulin aspart/insulin detemir
  • ceritinib
  • insulin glargine/insulin lispro
  • insulin aspart
  • insulin glulisine
  • insulin lispro
  • insulin glargine
  • protamine zinc insulin
Biomarker applications (based on IPA annotation)
  • prognosis
Wiki Pathways
  • AMPK signaling
  • DNA damage response (only ATM dependent)
  • Folate Metabolism
  • Insulin Signaling
  • Selenium Pathway
  • Type II diabetes mellitus
  • Vitamin B12 Metabolism
Pathway Interaction Database
  • Insulin Pathway
  • Insulin-mediated glucose transport
  • Signaling events mediated by PTP1B
  • Signaling events mediated by TCPTP
Reactome
  • IRS activation
  • Insulin receptor recycling
  • SHC activation
  • Signal attenuation
  • Signaling by Insulin receptor
Pathway Studio
  • InsulinR → CTNNB/FOXA/FOXO signaling
  • InsulinR → ELK-SRF/SREBF signaling
  • InsulinR → STAT signaling

All locus annotations are based on the sentinel SNP (rs8176720) and 10 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


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Genes hit or close-by
  • ABO ABO blood group (transferase A, alpha 1-3-N-acetylgalactosaminyltransferase; transferase B, alpha 1-3-galactosyltransferase)
eQTL genes
  • ABO ABO blood group (transferase A, alpha 1-3-N-acetylgalactosaminyltransferase; transferase B, alpha 1-3-galactosyltransferase)
  • SURF6 surfeit 6

 

Results from other genome-wide association studies

Trait P Study Source
cg14440550 (chr9:136131142) 3.3×10-310 10.1101/033084 (DOI) BIOS QTL cis-meQTLs
Plasma carcinoembryonic antigen (CEA) levels 5.2×10-51 23300138 (PMID) GRASP2 nonQTL
Soluble intercellular adhesion molecule 1 (ICAM-1) 4.8×10-22 21533024 (PMID) GRASP2 nonQTL
Anorexia nervosa 5.6×10-22 24514567 (PMID) Supplemental file
Serum alkaline phosphatase levels 3×10-21 24094242 (PMID) GWAS Catalog via SNiPA
LDL cholesterol 1.6×10-17 24097068 (PMID) Supplemental file
Hemoglobin (Hb) 1.4×10-12 23222517 (PMID) GRASP2 nonQTL
Alkaline phosphatase (ALP) 4.3×10-12 18940312 (PMID) GRASP2 nonQTL
Triglycerides 5.6×10-12 24097068 (PMID) Supplemental file
Red blood cell count (RBC) 2.2×10-11 23222517 (PMID) GRASP2 nonQTL
Hematocrit (Hct) 2.9×10-11 23222517 (PMID) GRASP2 nonQTL
Total cholesterol 6.5×10-8 20686565 (PMID) GRASP2 nonQTL
ADpSGEGDFXAEGGGVR* 2×10-7 24816252 (PMID) gwas.eu via SNiPA
Serum soluble E-selectin 7.2×10-7 19729612 (PMID) GRASP2 nonQTL
E-selectin 7.2×10-7 pha002871 (dbGaP) dbGaP via SNiPA
Esophageal squamous cell carcinoma (Esophageal cancer) 1.5×10-4 23300138 (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.