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

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Locus annotations

Locus 96

Top associations per target

Target cis/​trans Study SNP SNP location Maj/​min allele MAF N βinv seinv Pinv fclog Plog Praw
Coagulation Factor XI trans Discovery rs5030062 3:186,454,180 A/C 0.39 996 0.558 0.040 3×10-40 1.100 1.1×10-37 3.4×10-33
Coagulation Factor XI trans Replication rs710446 3:186,459,927 A/G 0.43 337 0.538 0.070 1.7×10-13 1.120 9.1×10-11 4.2×10-7
Prekallikrein trans Discovery rs5030062 3:186,454,180 A/C 0.39 996 0.519 0.040 1.8×10-35 1.080 5.7×10-27 4.4×10-34
Prekallikrein trans Replication rs5030062 3:186,454,180 A/C 0.38 337 0.444 0.070 8×10-10 1.100 2.4×10-9 1.1×10-9

 

Regional association plots

 

Boxplots and histograms for top associations

Coagulation Factor XI

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

Plasma kallikrein (Prekallikrein)

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

Coagulation Factor XI

Target (abbrv.) Coagulation Factor XI
Target (full name) Coagulation Factor XI
Somalogic ID (Sequence ID) SL002662 (2190-55_1)
Entrez Gene Symbol F11
UniProt ID P03951
UniProt Comment
  • Factor XI triggers the middle phase of the intrinsic pathway of blood coagulation by activating factor IX.
Wiki Pathways
  • Blood Clotting Cascade
Reactome
  • Intrinsic Pathway of Fibrin Clot Formation
Pathway Studio
  • Coagulation Cascade

Plasma kallikrein (Prekallikrein)

Target (abbrv.) Prekallikrein
Target (full name) Plasma kallikrein
Somalogic ID (Sequence ID) SL000545 (4152-58_2)
Entrez Gene Symbol KLKB1
UniProt ID P03952
UniProt Comment
  • The enzyme cleaves Lys-Arg and Arg-Ser bonds. It activates, in a reciprocal reaction, factor XII after its binding to a negatively charged surface. It also releases bradykinin from HMW kininogen and may also play a role in the renin-angiotensin system by converting prorenin into renin.
Targeted by drugs (based on IPA annotation)
  • aprotinin
  • ecallantide
Reactome
  • Activation of Matrix Metalloproteinases
  • Intrinsic Pathway of Fibrin Clot Formation
Pathway Studio
  • Coagulation Cascade

All locus annotations are based on the sentinel SNP (rs5030062) and 8 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

 

Results from other genome-wide association studies

Trait P Study Source
Activated partial thromboplastin time 1.9×10-203 22703881 (PMID) GRASP2 nonQTL
Activated Partial Thromboplastin Time 5.3×10-23 20303064 (PMID) GRASP2 nonQTL
bradykinin, des-arg(9) 5.9×10-13 24816252 (PMID) gwas.eu via SNiPA
Blood metabolite levels 6×10-13 24816252 (PMID) GWAS Catalog via SNiPA
Adiponectin levels 7.2×10-13 22479202 (PMID) GRASP2 nonQTL
Adiponectin levels (female) 3.3×10-12 22479202 (PMID) GRASP2 nonQTL
Activated Partial Thromboplastin Time (Female) 8.6×10-12 20303064 (PMID) GRASP2 nonQTL
Activated Partial Thromboplastin Time (Male) 2.1×10-11 20303064 (PMID) GRASP2 nonQTL
Plasma factor XI level and activated partial thromboplastin time 8×10-10 22701019 (PMID) GRASP2 nonQTL
Plasma renin activity levels 9×10-9 25477429 (PMID) GWAS Catalog via SNiPA
Gene expression of EIF2S3 in lymphoblastoid cell lines 4.9×10-7 17873877 (PMID) GRASP2 eQTL
Body mass index 4.7×10-5 22982992 (PMID) Supplemental file
Serum concentration of 4-vinylphenol sulfate 2.9×10-4 21886157 (PMID) GRASP2 metabQTL

Part of multiple cis/trans associations that involve proteins from vasodilatory and blood-coagulation pathways.

This locus harbours two replicated trans-pQTLs with Coagulation Factor XI (F11) and with Plasma kallikrein (KLKB1). rs5030062 tags the I581T coding variant rs710446 in KNG1 (kininogen 1). rs5030062 also associates with bradykinin in Shin et al. [PubMed] (p=5.94×10-13, see http://www.gwas.eu). Kininogen is a multi-domain protein and a precursor of vasodilator bradykinin via the kallikrein-kinin system. KNG1 also plays a role in blood coagulation as an activator of F11. This locus has been reported in GWAS with activated partial thromboplastin time (aPTT) [PubMed] and plasma renin activity [PubMed]. See Locus 138 for a cis-association with Plasma kallikrein (KLKB1) that also associates an association with bradykinin in Shin et al. [PubMed].

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.