HelmholtzZentrum munich
WCMC

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

ONLINE SUPPLEMENTARY INFORMATION

Ideogram
Proteome annotation
Locus annotations

Locus 353

Top associations per target

Target cis/​trans Study SNP SNP location Maj/​min allele MAF N βinv seinv Pinv fclog Plog Praw
IMDH1 trans Discovery rs1354034 3:56,849,749 C/T 0.38 995 -0.328 0.045 5.4×10-13 -1.130 1×10-10 0.002
IMDH1 trans Replication rs1354034 3:56,849,749 A/G 0.47 337 0.127 0.066 0.058 1.050 0.171 0.692
DLRB1 trans Discovery rs1354034 3:56,849,749 C/T 0.38 995 -0.294 0.044 6.1×10-11 -1.110 7.5×10-11 6.7×10-7
DLRB1 trans Replication rs1354034 3:56,849,749 A/G 0.47 337 0.120 0.045 0.009 1.110 0.005 0.004
AMPM2 trans Discovery rs1354034 3:56,849,749 C/T 0.38 995 -0.277 0.045 1.2×10-9 -1.060 2.4×10-8 1.8×10-9
AMPM2 trans Replication rs1354034 3:56,849,749 A/G 0.47 337 0.064 0.041 0.122 1.020 0.361 0.047

 

Regional association plots

Inosine-5'-monophosphate dehydrogenase 1 (IMDH1)

Dynein light chain roadblock-type 1 (DLRB1)

Methionine aminopeptidase 2 (AMPM2)

 

Boxplots and histograms for top associations

Inosine-5'-monophosphate dehydrogenase 1 (IMDH1)

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

Dynein light chain roadblock-type 1 (DLRB1)

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

Methionine aminopeptidase 2 (AMPM2)

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

Inosine-5'-monophosphate dehydrogenase 1 (IMDH1)

Target (abbrv.) IMDH1
Target (full name) Inosine-5'-monophosphate dehydrogenase 1
Somalogic ID (Sequence ID) SL014735 (5229-90_3)
Entrez Gene Symbol IMPDH1
UniProt ID P20839
UniProt Comment
  • Catalyzes the conversion of inosine 5'-phosphate (IMP) to xanthosine 5'-phosphate (XMP), the first committed and rate-limiting step in the de novo synthesis of guanine nucleotides, and therefore plays an important role in the regulation of cell growth. Could also have a single-stranded nucleic acid-binding activity and could play a role in RNA and/or DNA metabolism. It may also have a role in the development of malignancy and the growth progression of some tumors.
Targeted by drugs (based on IPA annotation)
  • thioguanine
  • VX-944
  • pegintron/ribavirin
  • PEG-interferon alfa-2a/ribavirin
  • nitazoxanide/peginterferon alfa-2a/ribavirin
  • interferon alfa-2b/ribavirin
  • mycophenolate mofetil
  • mycophenolic acid
  • ribavirin

Dynein light chain roadblock-type 1 (DLRB1)

Target (abbrv.) DLRB1
Target (full name) Dynein light chain roadblock-type 1
Somalogic ID (Sequence ID) SL011530 (3845-51_2)
Entrez Gene Symbol DYNLRB1
UniProt ID Q9NP97
UniProt Comment
  • Acts as one of several non-catalytic accessory components of the cytoplasmic dynein 1 complex that are thought to be involved in linking dynein to cargos and to adapter proteins that regulate dynein function. Cytoplasmic dynein 1 acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules.
Pathway Interaction Database
  • TGF-beta receptor signaling
Reactome
  • Intraflagellar transport

Methionine aminopeptidase 2 (AMPM2)

Target (abbrv.) AMPM2
Target (full name) Methionine aminopeptidase 2
Somalogic ID (Sequence ID) SL007261 (3170-6_1)
Entrez Gene Symbol METAP2
UniProt ID P50579
UniProt Comment
  • Cotranslationally removes the N-terminal methionine from nascent proteins. The N-terminal methionine is often cleaved when the second residue in the primary sequence is small and uncharged (Met-Ala-, Cys, Gly, Pro, Ser, Thr, or Val). The catalytic activity of human METAP2 toward Met-Val peptides is consistently two orders of magnitude higher than that of METAP1, suggesting that it is responsible for processing proteins containing N-terminal Met-Val and Met-Thr sequences in vivo.
Targeted by drugs (based on IPA annotation)
  • nitroxoline
  • beloranib
  • PPI-2458
Biomarker applications (based on IPA annotation)
  • unspecified application

All locus annotations are based on the sentinel SNP (rs1354034).
Download the detailed results of SNiPA's block annotation (PDF)

Linked genes

Genes hit or close-by
  • ARHGEF3 Rho guanine nucleotide exchange factor (GEF) 3
Potentially regulated genes
  • CCDC66 coiled-coil domain containing 66
  • ARHGEF3 Rho guanine nucleotide exchange factor (GEF) 3

 

Results from other genome-wide association studies

Trait P Study Source
Mean platelet volume 3×10-69 22139419 (PMID) GWAS Catalog via SNiPA
Mean platelet volume (MPV) 3.3×10-69 22139419 (PMID) GRASP2 nonQTL
Platelet count (PLT) 2.9×10-54 22139419 (PMID) GRASP2 nonQTL
Platelet counts 3×10-54 22139419 (PMID) GWAS Catalog via SNiPA
Platelet count 1.1×10-19 23263863 (PMID) GRASP2 nonQTL
Hematological traits (Red blood cell count, Hemoglobin concentration, Hematocrit, Mean corpuscular hemoglobin, MCH concentration, Mean corpuscular volume, Platelet count and White blood cell count) 9.3×10-13 23263863 (PMID) GRASP2 nonQTL

Functional match between Guanine Nucleotide Exchange Factor in cis and Inosine-5'-monophosphate dehydrogenase in trans.

This locus harbours a non-replicated trans-pQTL to Inosine-5'-monophosphate dehydrogenase 1 (IMPDH1). Gieger et al. [PubMed] report this locus as a platelet count GWAS hit with ARHGEF3 (Rho Guanine Nucleotide Exchange Factor (GEF) 3) as functional gene. Gieger et al. showed that ablation of ARHGEF3 in D. rerio has profound effect on thrombopoiesis and erythropoiesis. Diseases associated with ARHGEF3 include osteoporosis. ARHGEF3 and IMPDH1 are functionally linked, since IMPDH1 catalyses the first step of the guanine ribonucleotide biosynthesis. This locus also has many trans-eQTLs (N=203); also trans-association with Dynein light chain roadblock-type 1 (DYNLRB1) and Methionine aminopeptidase 2 (METAP2) and several less significant associations. This locus also associates weakly in KORA with IMPDH2 (p=1.3×10-7).

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.