HelmholtzZentrum munich
WCMC

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

ONLINE SUPPLEMENTARY INFORMATION

Ideogram
Proteome annotation
Locus annotations

Locus 442

Top associations per target

Target cis/​trans Study SNP SNP location Maj/​min allele MAF N βinv seinv Pinv fclog Plog Praw
sTie-1 trans Discovery rs7857390 9:136,128,546 G/A 0.38 996 -0.295 0.045 5.8×10-11 -1.050 6.3×10-11 1.7×10-10
sTie-1 trans Replication rs7857390 9:136,128,546 G/A 0.34 337 -0.329 0.066 1×10-6 -1.080 4×10-6 1.5×10-5

 

Regional association plots

Tyrosine-protein kinase receptor Tie-1, soluble (sTie-1)

 

Boxplots and histograms for top associations

Tyrosine-protein kinase receptor Tie-1, soluble (sTie-1)

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

Tyrosine-protein kinase receptor Tie-1, soluble (sTie-1)

Target (abbrv.) sTie-1
Target (full name) Tyrosine-protein kinase receptor Tie-1, soluble
Somalogic ID (Sequence ID) SL003199 (2844-53_2)
Entrez Gene Symbol TIE1
UniProt ID P35590
UniProt Comment
  • Transmembrane tyrosine-protein kinase that may modulate TEK/TIE2 activity and contribute to the regulation of angiogenesis.

All locus annotations are based on the sentinel SNP (rs7857390) and 15 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)
eQTL genes
  • ABO ABO blood group (transferase A, alpha 1-3-N-acetylgalactosaminyltransferase; transferase B, alpha 1-3-galactosyltransferase)
  • SURF1 surfeit 1
  • SLC2A6 solute carrier family 2 (facilitated glucose transporter), member 6
  • GBGT1 globoside alpha-1,3-N-acetylgalactosaminyltransferase 1

 

Results from other genome-wide association studies

Trait P Study Source
Activated partial thromboplastin time 8.2×10-39 22703881 (PMID) GRASP2 nonQTL
von Willebrand factor (vWF) 6.1×10-22 23381943 (PMID) GRASP2 nonQTL
Blood soluble E-selectin levels (female) 1.7×10-20 20147318 (PMID) GRASP2 nonQTL
Soluble intercellular adhesion molecule 1 (ICAM-1) 2.8×10-17 21533024 (PMID) GRASP2 nonQTL
Venous thrombosis 4×10-14 22675575 (PMID) GRASP2 nonQTL
Factor XIII antigen 4.9×10-13 23381943 (PMID) GRASP2 nonQTL
Alkaline phosphatase (ALP) 3.7×10-12 18940312 (PMID) GRASP2 nonQTL
Blood soluble E-selectin levels (in non-diabetic females) 2.5×10-9 20147318 (PMID) GRASP2 nonQTL
LDL cholesterol 8.6×10-8 24097068 (PMID) Supplemental file
Blood soluble E-selectin levels (in diabetic females) 8.8×10-8 20147318 (PMID) GRASP2 nonQTL
Triglycerides 7.8×10-7 24097068 (PMID) Supplemental file
ADSGEGDFXAEGGGVR* 1.2×10-6 24816252 (PMID) gwas.eu via SNiPA
Venous thromboembolism 4.2×10-6 22672568 (PMID) GRASP2 nonQTL
Total cholesterol 6.6×10-6 20686565 (PMID) GRASP2 nonQTL
Gene expression of ABO in normal prepouch ileum 3.4×10-4 23474282 (PMID) GRASP2 eQTL

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.