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

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Locus annotations

Locus 417

Top associations per target

Target cis/​trans Study SNP SNP location Maj/​min allele MAF N βinv seinv Pinv fclog Plog Praw
EDAR trans Discovery rs16873418 8:106,592,145 A/G 0.30 997 0.315 0.046 1.9×10-11 1.120 1.9×10-11 3.1×10-7
EDAR trans Replication rs4734879 8:106,583,124 A/G 0.42 337 0.216 0.049 1.5×10-5 1.120 2.9×10-5 0.001
Integrin a1b1 trans Discovery rs16873418 8:106,592,145 A/G 0.30 997 0.280 0.046 1.4×10-9 1.090 6.9×10-10 9.1×10-11
Integrin a1b1 trans Replication rs4734879 8:106,583,124 A/G 0.42 337 0.099 0.063 0.114 1.040 0.189 0.694

 

Regional association plots

Tumor necrosis factor receptor superfamily member EDAR (EDAR)

Download the association data used to generate this plot

Integrin alpha-I: beta-1 complex (Integrin a1b1)

Download the association data used to generate this plot

 

Boxplots and histograms for top associations

Tumor necrosis factor receptor superfamily member EDAR (EDAR)

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

Integrin alpha-I: beta-1 complex (Integrin a1b1)

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

Tumor necrosis factor receptor superfamily member EDAR (EDAR)

Target (abbrv.) EDAR
Target (full name) Tumor necrosis factor receptor superfamily member EDAR
Somalogic ID (Sequence ID) SL004872 (2977-7_2)
Entrez Gene Symbol EDAR
UniProt ID Q9UNE0
UniProt Comment
  • Receptor for EDA isoform A1, but not for EDA isoform A2. Mediates the activation of NF-kappa-B and JNK. May promote caspase-independent cell death.
Wiki Pathways
  • Integrated Breast Cancer Pathway
Pathway Studio
  • Apoptosis
  • EctodysplasinR → AP-1 signaling
  • EctodysplasinR → LEF1 signaling
  • EctodysplasinR → NF-kB signaling

Integrin alpha-I: beta-1 complex (Integrin a1b1)

Target (abbrv.) Integrin a1b1
Target (full name) Integrin alpha-I: beta-1 complex
Somalogic ID (Sequence ID) SL003179 (3503-4_2)
Entrez Gene Symbol ITGA1, ITGB1
UniProt ID P56199, P05556
UniProt Comment
  • P56199: Integrin alpha-1/beta-1 is a receptor for laminin and collagen. It recognizes the proline-hydroxylated sequence G-F-P-G-E-R in collagen. Involved in anchorage-dependent, negative regulation of EGF-stimulated cell growth.
  • P05556: Integrins alpha-1/beta-1, alpha-2/beta-1, alpha-10/beta-1 and alpha-11/beta-1 are receptors for collagen. Integrins alpha-1/beta-1 and alpha-2/beta-2 recognize the proline-hydroxylated sequence G-F-P-G-E-R in collagen. Integrins alpha-2/beta-1, alpha-3/beta-1, alpha-4/beta-1, alpha-5/beta-1, alpha-8/beta-1, alpha-10/beta-1, alpha-11/beta-1 and alpha-V/beta-1 are receptors for fibronectin. Alpha-4/beta-1 recognizes one or more domains within the alternatively spliced CS-1 and CS-5 regions of fibronectin. Integrin alpha-5/beta-1 is a receptor for fibrinogen. Integrin alpha-1/beta-1, alpha-2/beta-1, alpha-6/beta-1 and alpha-7/beta-1 are receptors for lamimin. Integrin alpha-4/beta-1 is a receptor for VCAM1. It recognizes the sequence Q-I-D-S in VCAM1. Integrin alpha-9/beta-1 is a receptor for VCAM1, cytotactin and osteopontin. It recognizes the sequence A-E-I-D-G-I-E-L in cytotactin. Integrin alpha-3/beta-1 is a receptor for epiligrin, thrombospondin and CSPG4. Alpha-3/beta-1 may mediate with LGALS3 the stimulation by CSPG4 of endothelial cells migration. Integrin alpha-V/beta-1 is a receptor for vitronectin. Beta-1 integrins recognize the sequence R-G-D in a wide array of ligands. Isoform 2 interferes with isoform 1 resulting in a dominant negative effect on cell adhesion and migration (in vitro). When associated with alpha-7/beta-1 integrin, regulates cell adhesion and laminin matrix deposition. Involved in promoting endothelial cell motility and angiogenesis. Involved in osteoblast compaction through the fibronectin fibrillogenesis cell-mediated matrix assembly process and the formation of mineralized bone nodules. May be involved in up-regulation of the activity of kinases such as PKC via binding to KRT1. Together with KRT1 and RACK1, serves as a platform for SRC activation or inactivation. Plays a mechanistic adhesive role during telophase, required for the successful completion of cytokinesis. Integrin alpha-3/beta-1 provides a docking site for FAP (seprase) at invadopodia plasma membranes in a collagen-dependent manner and hence may participate in the adhesion, formation of invadopodia and matrix degradation processes, promoting cell invasion.
Wiki Pathways
  • Integrin-mediated cell adhesion
  • Regulation of Actin Cytoskeleton
  • Signaling of Hepatocyte Growth Factor Receptor
Pathway Interaction Database
  • Arf6 trafficking events
  • Beta1 integrin cell surface interactions
  • CXCR4-mediated signaling events
  • Integrin family cell surface interactions
  • Plexin-D1 Signaling
  • Signaling events mediated by PRL
  • Signaling events mediated by TCPTP
  • VEGFR3 signaling in lymphatic endothelium
Reactome
  • CHL1 interactions
  • Integrin cell surface interactions
  • Laminin interactions
  • Other semaphorin interactions
  • Platelet Adhesion to exposed collagen
  • Smooth Muscle Contraction

All locus annotations are based on the sentinel SNP (rs16873418) 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
  • ZFPM2 zinc finger protein, FOG family member 2
eQTL genes
  • CXCL5 chemokine (C-X-C motif) ligand 5

 

Results from other genome-wide association studies

Trait P Study Source
Serum vascular endothelial growth factor (VEGF) 5.5×10-30 21757650 (PMID) GRASP2 nonQTL
Vascular endothelial growth factor levels 5×10-23 21757650 (PMID) GWAS Catalog via SNiPA
Platelet counts 4×10-17 22139419 (PMID) GWAS Catalog via SNiPA
Platelet count (PLT) 4.3×10-17 22139419 (PMID) GRASP2 nonQTL

Possible link between cis-variants and protein levels of EDAR, possible role in morphogenesis.

This locus harbours a replicated trans-pQTL to Tumor necrosis factor receptor superfamily member EDAR (EDAR). It also harbours a non-replicated trans-pQTL to the Integrin alpha-I: beta-1 complex (ITGA1/ITGB1). The protein encoded at this locus is Zinc Finger Protein, FOG Family Member 2 (ZFPM2). It is a transcription regulator that plays a central role in heart morphogenesis and development of coronary vessels from epicardium, by regulating genes that are essential during cardiogenesis. Association with EDAR, a member of the tumour necrosis factor receptor family, can activate the nuclear factor-kappaB, JNK, and caspase-independent cell death pathways. There is thus a potential (but weak) link to morphogenesis – however, EDAR was so far only linked to ectodermal development. This locus is also a GWAS hit for Vascular endothelial growth factor levels and Platelet counts.

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.