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

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Locus annotations

Locus 79

Top associations per target

Target cis/​trans Study SNP SNP location Maj/​min allele MAF N βinv seinv Pinv fclog Plog Praw
CAMK1 trans Discovery rs7091871 10:101,810,304 C/T 0.06 995 1.305 0.084 1×10-48 1.480 4.2×10-61 6.9×10-48
CAMK1 trans Replication rs78723267 10:101,798,405 G/A 0.06 337 1.072 0.125 3.5×10-16 1.330 1.2×10-15 3×10-18
Calpastatin trans Discovery rs7091871 10:101,810,304 C/T 0.06 995 -0.576 0.080 1.4×10-12 -1.170 1.1×10-10 5.2×10-5
Calpastatin trans Replication rs78723267 10:101,798,405 G/A 0.06 337 -0.738 0.138 1.7×10-7 -1.220 4.3×10-6 0.005

 

Regional association plots

 

Boxplots and histograms for top associations

Calcium/calmodulin-dependent protein kinase type 1 (CAMK1)

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

Calpastatin

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

Calcium/calmodulin-dependent protein kinase type 1 (CAMK1)

Target (abbrv.) CAMK1
Target (full name) Calcium/calmodulin-dependent protein kinase type 1
Somalogic ID (Sequence ID) SL010489 (3592-4_3)
Entrez Gene Symbol CAMK1
UniProt ID Q14012
UniProt Comment
  • Calcium/calmodulin-dependent protein kinase that operates in the calcium-triggered CaMKK-CaMK1 signaling cascade and, upon calcium influx, regulates transcription activators activity, cell cycle, hormone production, cell differentiation, actin filament organization and neurite outgrowth. Recognizes the substrate consensus sequence [MVLIF]-x-R-x(2)-[ST]-x(3)-[MVLIF]. Regulates axonal extension and growth cone motility in hippocampal and cerebellar nerve cells. Upon NMDA receptor-mediated Ca(2+) elevation, promotes dendritic growth in hippocampal neurons and is essential in synapses for full long-term potentiation (LTP) and ERK2-dependent translational activation. Downstream of NMDA receptors, promotes the formation of spines and synapses in hippocampal neurons by phosphorylating ARHGEF7/BETAPIX on 'Ser-694', which results in the enhancement of ARHGEF7 activity and activation of RAC1. Promotes neuronal differentiation and neurite outgrowth by activation and phosphorylation of MARK2 on 'Ser-91', 'Ser-92', 'Ser-93' and 'Ser-294'. Promotes nuclear export of HDAC5 and binding to 14-3-3 by phosphorylation of 'Ser-259' and 'Ser-498' in the regulation of muscle cell differentiation. Regulates NUMB-mediated endocytosis by phosphorylation of NUMB on 'Ser-276' and 'Ser-295'. Involved in the regulation of basal and estrogen-stimulated migration of medulloblastoma cells through ARHGEF7/BETAPIX phosphorylation (By similarity). Is required for proper activation of cyclin-D1/CDK4 complex during G1 progression in diploid fibroblasts. Plays a role in K(+) and ANG2-mediated regulation of the aldosterone synthase (CYP11B2) to produce aldosterone in the adrenal cortex. Phosphorylates EIF4G3/eIF4GII. In vitro phosphorylates CREB1, ATF1, CFTR, MYL9 and SYN1/synapsin I.
Wiki Pathways
  • Calcium Regulation in the Cardiac Cell
Pathway Studio
  • EGFR/ERBB3 → MEF/MYOD/NFATC/MYOG signaling
  • GABA(B)R → postsynaptic inhibition
  • NPY1R → CRH/POMC production
  • NeuropeptideYR → ATF/CREB signaling
  • VasopressinR1 → MEF/MYOD/NFATC/MYOG signaling
  • VasopressinR2 → MEF/MYOD/NFATC/MYOG signaling

Calpastatin

Target (abbrv.) Calpastatin
Target (full name) Calpastatin
Somalogic ID (Sequence ID) SL000338 (3026-5_2)
Entrez Gene Symbol CAST
UniProt ID P20810
UniProt Comment
  • Specific inhibition of calpain (calcium-dependent cysteine protease). Plays a key role in postmortem tenderization of meat and have been proposed to be involved in muscle protein degradation in living tissue.

All locus annotations are based on the sentinel SNP (rs7091871) and 11 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
  • CPN1 carboxypeptidase N, polypeptide 1
eQTL genes
  • HIF1AN hypoxia inducible factor 1, alpha subunit inhibitor

 

Results from other genome-wide association studies


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No associations available.

Variation in CPN1 may modify calpain-induced proteolysis via CAMK1 and CAST.

This locus harbours two replicated trans-pQTLs, one with Calcium/calmodulin-dependent protein kinase type 1 (CAMK1) and one with Calpastatin (CAST). CAST is an endogenous calcium-dependent cysteine protease (calpain) inhibitor. CAST and CAMK1 are hence both calcium-regulated. rs7091871 tags variants close to Carboxypeptidase N (CPN1) protects the body from potent vasoactive and inflammatory peptides containing C-terminal Arg or Lys (such as kinins or anaphylatoxins) which are released into the circulation. This trans-pQTL hence links variation in CPN1, CAMK1, and CAST in the regulation of calcium-dependent calpain-induced proteolysis. See Locus 17 and Locus 413 for a replicated trans-pQTL with CAMK1 a different chromosome.

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.