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

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Locus annotations

Locus 115

Top associations per target

Target cis/​trans Study SNP SNP location Maj/​min allele MAF N βinv seinv Pinv fclog Plog Praw
C1r cis Discovery rs12146727 12:7,170,336 G/A 0.13 996 -0.780 0.061 3.4×10-35 -1.150 5.8×10-16 1.3×10-32
C1r cis Replication rs11838267 12:7,175,872 A/G 0.09 337 -0.656 0.126 3.6×10-7 -1.270 3.8×10-7 2.4×10-6
C1q trans Discovery rs12146727 12:7,170,336 G/A 0.13 996 -0.509 0.063 2×10-15 -1.080 1.4×10-9 9.7×10-13
C1q trans Replication rs11064498 12:7,171,507 A/G 0.09 337 -0.543 0.120 8.8×10-6 -1.090 3.8×10-5 1.1×10-4

 

Regional association plots

 

Boxplots and histograms for top associations

Complement C1r subcomponent (C1r)

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

Complement C1q subcomponent (C1q)

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

Complement C1r subcomponent (C1r)

Target (abbrv.) C1r
Target (full name) Complement C1r subcomponent
Somalogic ID (Sequence ID) SL000310 (3285-23_2)
Entrez Gene Symbol C1R
UniProt ID P00736
UniProt Comment
  • C1r B chain is a serine protease that combines with C1q and C1s to form C1, the first component of the classical pathway of the complement system.
Targeted by drugs (based on IPA annotation)
  • SERPING1
Reactome
  • Classical antibody-mediated complement activation
  • Initial triggering of complement
Pathway Studio
  • Classical Complement Pathway

Complement C1q subcomponent (C1q)

Target (abbrv.) C1q
Target (full name) Complement C1q subcomponent
Somalogic ID (Sequence ID) SL000309 (2753-2_2)
Entrez Gene Symbol C1QA, C1QB, C1QC
UniProt ID P02745, P02746, P02747
UniProt Comment
  • P02745: C1q associates with the proenzymes C1r and C1s to yield C1, the first component of the serum complement system. The collagen-like regions of C1q interact with the Ca(2+)-dependent C1r(2)C1s(2) proenzyme complex, and efficient activation of C1 takes place on interaction of the globular heads of C1q with the Fc regions of IgG or IgM antibody present in immune complexes.
  • P02746: C1q associates with the proenzymes C1r and C1s to yield C1, the first component of the serum complement system. The collagen-like regions of C1q interact with the Ca(2+)-dependent C1r(2)C1s(2) proenzyme complex, and efficient activation of C1 takes place on interaction of the globular heads of C1q with the Fc regions of IgG or IgM antibody present in immune complexes.
  • P02747: C1q associates with the proenzymes C1r and C1s to yield C1, the first component of the serum complement system. The collagen-like regions of C1q interact with the Ca(2+)-dependent C1r(2)C1s(2) proenzyme complex, and efficient activation of C1 takes place on interaction of the globular heads of C1q with the Fc regions of IgG or IgM antibody present in immune complexes.
Wiki Pathways
  • Complement Activation, Classical Pathway
  • Complement and Coagulation Cascades
Reactome
  • Classical antibody-mediated complement activation
  • Initial triggering of complement

All locus annotations are based on the sentinel SNP (rs12146727) and 16 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
  • C1S complement component 1, s subcomponent
Potentially regulated genes
  • C1S complement component 1, s subcomponent
  • C1S
eQTL genes
  • C1S complement component 1, s subcomponent
  • C1RL complement component 1, r subcomponent-like

 

Results from other genome-wide association studies

Trait P Study Source
Hepatitis C virus (HCV)-induced liver fibrosis 3.3×10-6 22841784 (PMID) GRASP2 nonQTL
Alzheimer's disease 5.7×10-6 24162737 (PMID) Supplemental file
cg07027613 (chr12:7260584) 9.6×10-6 10.1101/033084 (DOI) BIOS QTL cis-meQTLs
Coronary artery disease (CAD) 2.3×10-5 23202125 (PMID) GRASP2 nonQTL
Myocardial infarction (MI), sudden cardiac arrest in patients with coronary artery disease (CAD) 3.6×10-5 21658281 (PMID) GRASP2 nonQTL
Coronary artery disease and myocardial infarction 5.9×10-5 23202125 (PMID) Supplemental file
cg24535475 (chr12:7167924) 9.7×10-5 10.1101/033084 (DOI) BIOS QTL cis-meQTLs
Allele-specific Expression Patterns in human glioblastoma cell line U87MG 1.6×10-4 22467206 (PMID) GRASP2 eQTL

C1R may regulate C1S, indicates role of genetic variant in AD and CVD

This locus harbours a replicated trans-pQTLS to Complement C1q subcomponent (C1QA C1QB C1QC) and a replicated cis-pQTL to Complement C1r subcomponent (C1R). There is also a weak association in KORA (p=1.8×10-7) with Complement C4b (C4A/C4B). Functional match between in CS1 and C1q complex, nominal association with AD (st12_comb p=5.7×10-6, note that association strengthens when including more samples: st1 p=3.1×10-5) and with CVD (Cardiogam p=5.9×10-5).

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.