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

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Locus annotations

Locus 82

Top associations per target

Target cis/​trans Study SNP SNP location Maj/​min allele MAF N βinv seinv Pinv fclog Plog Praw
Semaphorin 3A trans Discovery rs2239908 17:26,725,265 A/G 0.46 993 -0.617 0.040 9.5×10-48 -1.110 1.5×10-23 1.6×10-7
Semaphorin 3A trans Replication rs704 17:26,694,861 A/G 0.49 337 -0.411 0.063 3.1×10-10 -1.100 5.4×10-8 5.5×10-6
CAMK1D trans Discovery rs2239908 17:26,725,265 A/G 0.46 993 -0.446 0.043 3×10-24 -1.060 1.2×10-8 0.041
CAMK1D trans Replication rs704 17:26,694,861 A/G 0.49 337 -0.386 0.068 3.9×10-8 -1.050 0.004 0.662
IL-5 trans Discovery rs2239908 17:26,725,265 A/G 0.46 993 0.434 0.042 4.8×10-24 1.070 1.8×10-20 2.2×10-15
IL-5 trans Replication rs704 17:26,694,861 A/G 0.49 337 0.166 0.071 0.02 1.030 0.2 0.381
WISP-1 trans Discovery rs2239908 17:26,725,265 A/G 0.46 993 -0.288 0.044 1.1×10-10 -1.070 4.3×10-10 7.1×10-6
WISP-1 trans Replication rs704 17:26,694,861 A/G 0.49 337 -0.238 0.060 7.7×10-5 -1.070 3.9×10-5 1.3×10-4
Cytidylate kinase trans Discovery rs2239908 17:26,725,265 A/G 0.46 993 0.270 0.044 8×10-10 1.050 2.1×10-8 0.001
Cytidylate kinase trans Replication rs704 17:26,694,861 A/G 0.49 337 0.200 0.072 0.006 1.050 0.009 0.023
Marapsin trans Discovery rs2239908 17:26,725,265 A/G 0.46 993 0.264 0.043 1.6×10-9 1.040 6.7×10-6 0.001
Marapsin trans Replication rs704 17:26,694,861 A/G 0.49 337 0.180 0.070 0.011 1.040 0.064 0.441

 

Regional association plots

Semaphorin-3A (Semaphorin 3A)

Download the association data used to generate this plot

Calcium/calmodulin-dependent protein kinase type 1D (CAMK1D)

Download the association data used to generate this plot

Interleukin-5 (IL-5)

Download the association data used to generate this plot

WNT1-inducible-signaling pathway protein 1 (WISP-1)

Download the association data used to generate this plot

UMP-CMP kinase (Cytidylate kinase)

Download the association data used to generate this plot

Serine protease 27 (Marapsin)

Download the association data used to generate this plot

 

Boxplots and histograms for top associations

Semaphorin-3A (Semaphorin 3A)

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

Calcium/calmodulin-dependent protein kinase type 1D (CAMK1D)

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

Interleukin-5 (IL-5)

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

WNT1-inducible-signaling pathway protein 1 (WISP-1)

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

UMP-CMP kinase (Cytidylate kinase)

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

Serine protease 27 (Marapsin)

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

Semaphorin-3A (Semaphorin 3A)

Target (abbrv.) Semaphorin 3A
Target (full name) Semaphorin-3A
Somalogic ID (Sequence ID) SL010379 (3222-11_2)
Entrez Gene Symbol SEMA3A
UniProt ID Q14563
UniProt Comment
  • Involved in the development of the olfactory system and in neuronal control of puberty. Induces the collapse and paralysis of neuronal growth cones. Could serve as a ligand that guides specific growth cones by a motility-inhibiting mechanism. Binds to the complex neuropilin-1/plexin-1.
Wiki Pathways
  • angiogenesis overview
Reactome
  • CRMPs in Sema3A signaling
  • SEMA3A-Plexin repulsion signaling by inhibiting Integrin adhesion
  • Sema3A PAK dependent Axon repulsion

Calcium/calmodulin-dependent protein kinase type 1D (CAMK1D)

Target (abbrv.) CAMK1D
Target (full name) Calcium/calmodulin-dependent protein kinase type 1D
Somalogic ID (Sequence ID) SL010490 (3418-12_2)
Entrez Gene Symbol CAMK1D
UniProt ID Q8IU85
UniProt Comment
  • Calcium/calmodulin-dependent protein kinase that operates in the calcium-triggered CaMKK-CaMK1 signaling cascade and, upon calcium influx, activates CREB-dependent gene transcription, regulates calcium-mediated granulocyte function and respiratory burst and promotes basal dendritic growth of hippocampal neurons. In neutrophil cells, required for cytokine-induced proliferative responses and activation of the respiratory burst. Activates the transcription factor CREB1 in hippocampal neuron nuclei. May play a role in apoptosis of erythroleukemia cells. In vitro, phosphorylates transcription factor CREM isoform Beta.

Interleukin-5 (IL-5)

Target (abbrv.) IL-5
Target (full name) Interleukin-5
Somalogic ID (Sequence ID) SL000481 (3741-4_3)
Entrez Gene Symbol IL5
UniProt ID P05113
UniProt Comment
  • Factor that induces terminal differentiation of late-developing B-cells to immunoglobulin secreting cells.
Biomarker applications (based on IPA annotation)
  • diagnosis
  • efficacy
  • response to therapy

WNT1-inducible-signaling pathway protein 1 (WISP-1)

Target (abbrv.) WISP-1
Target (full name) WNT1-inducible-signaling pathway protein 1
Somalogic ID (Sequence ID) SL004689 (3057-55_1)
Entrez Gene Symbol WISP1
UniProt ID O95388
UniProt Comment
  • Downstream regulator in the Wnt/Frizzled-signaling pathway. Associated with cell survival. Attenuates p53-mediated apoptosis in response to DNA damage through activation of AKT kinase. Up-regulates the anti-apoptotic Bcl-X(L) protein. Adheres to skin and melanoma fibroblasts. In vitro binding to skin fibroblasts occurs through the proteoglycans, decorin and biglycan.

UMP-CMP kinase (Cytidylate kinase)

Target (abbrv.) Cytidylate kinase
Target (full name) UMP-CMP kinase
Somalogic ID (Sequence ID) SL007871 (4786-58_3)
Entrez Gene Symbol CMPK1
UniProt ID P30085
UniProt Comment
  • Catalyzes the phosphorylation of pyrimidine nucleoside monophosphates at the expense of ATP. Plays an important role in de novo pyrimidine nucleotide biosynthesis. Has preference for UMP and CMP as phosphate acceptors. Also displays broad nucleoside diphosphate kinase activity.

Serine protease 27 (Marapsin)

Target (abbrv.) Marapsin
Target (full name) Serine protease 27
Somalogic ID (Sequence ID) SL011069 (3624-3_4)
Entrez Gene Symbol PRSS27
UniProt ID Q9BQR3
UniProt Comment
  • Secreted

All locus annotations are based on the sentinel SNP (rs2239908) and 18 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
eQTL genes

 

Results from other genome-wide association studies

Trait P Study Source
cg20687875 (chr17:26647189) 1.6×10-46 10.1101/033084 (DOI) BIOS QTL cis-meQTLs
Gene expression of TMEM97///IFT20 in blood 3.1×10-23 21829388 (PMID) GRASP2 eQTL
Gene expression of SARM1 in peripheral blood monocytes 3.5×10-17 20502693 (PMID) GRASP2 eQTL
Gene expression of SARM1///SLC46A1 in blood 1.7×10-14 21829388 (PMID) GRASP2 eQTL
cg02062123 (chr17:26733607) 8.6×10-9 10.1101/033084 (DOI) BIOS QTL cis-meQTLs
cg04010423 (chr17:26732144) 1.1×10-7 10.1101/033084 (DOI) BIOS QTL cis-meQTLs
Gene expression of SPA17 in peripheral blood monocytes 2.5×10-6 20502693 (PMID) GRASP2 eQTL
Gene expression of CLDN16 in peripheral blood monocytes 5.9×10-6 20502693 (PMID) GRASP2 eQTL
cg08473663 (chr17:26695414) 1.4×10-5 10.1101/033084 (DOI) BIOS QTL cis-meQTLs
Gene expression of TMEM199 in normal prepouch ileum 1.6×10-5 23474282 (PMID) GRASP2 eQTL
Advanced age-related macular degeneration (choroidal neovascularization) vs. no AMD 2.6×10-5 23455636 (PMID) GRASP2 nonQTL
cg24339470 (chr17:26712436) 3.8×10-5 10.1101/033084 (DOI) BIOS QTL cis-meQTLs
Ankylosing spondylitis 6.8×10-5 22138694 (PMID) GRASP2 nonQTL
cg01641371 (chr17:26712068) 7.6×10-5 10.1101/033084 (DOI) BIOS QTL cis-meQTLs
Educational attainment, Education years 4.4×10-4 23722424 (PMID) Supplemental file
Years of education 4.4×10-4 23722424 (PMID) GRASP2 nonQTL

This locus links multiple proteins (SEMA3A, CAMK1D, WISP1, and IL5) through trans-associations, including associations with opposite directions.

This locus harbours three replicated trans-pQTLs, with Semaphorin-3A (SEMA3A), with Calcium/calmodulin-dependent protein kinase type 1D (CAMK1D), and with WNT1-inducible-signaling pathway protein 1 (WISP1), and three further non-replicated, but nominally significant associations with identical trends, with Interleukin-5 (IL5), UMP-CMP kinase (CMPK1), and Serine protease 27 (PRSS27). Interestingly, ratios between SEMA3A and Interleukin-5 (IL5) display a large increase in the strength of association (p-gain=1.1×1017, replicated p-gain=1.3×105 in QMDiab). Ratios of CAMK1D also displays a large p-gain (p-gain=8.0×1016 in KORA, p-gain=8.0×102 in QMDiab, indicating that the genetics variant either hits a pathway in which SEMA3A and CAMK1D are either regulated in opposed directions to IL5, or where IL5 protein levels play a normalizing role. There a multiple candidate genes for the causative cis-gene at this locus, including TMEM97, which has a strong eQTL that is tagged by rs2239908 (see SNiPA annotation for details).

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.