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

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Locus annotations

Locus 7

Top associations per target

Target cis/​trans Study SNP SNP location Maj/​min allele MAF N βinv seinv Pinv fclog Plog Praw
Siglec-3 cis Discovery rs12459419 19:51,728,477 C/T 0.28 995 -1.133 0.034 2.9×10-165 -1.610 1.4×10-185 2.7×10-167
Siglec-3 cis Replication rs3865444 19:51,727,962 C/A 0.17 337 -1.028 0.056 2×10-52 -1.590 1.5×10-59 4.2×10-41

 

Regional association plots

Myeloid cell surface antigen CD33 (Siglec-3)

Download the association data used to generate this plot

 

Boxplots and histograms for top associations

Myeloid cell surface antigen CD33 (Siglec-3)

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

Myeloid cell surface antigen CD33 (Siglec-3)

Target (abbrv.) Siglec-3
Target (full name) Myeloid cell surface antigen CD33
Somalogic ID (Sequence ID) SL005215 (3166-92_1)
Entrez Gene Symbol CD33
UniProt ID P20138
UniProt Comment
  • Putative adhesion molecule of myelomonocytic-derived cells that mediates sialic-acid dependent binding to cells. Preferentially binds to alpha-2,6-linked sialic acid. The sialic acid recognition site may be masked by cis interactions with sialic acids on the same cell surface. In the immune response, may act as an inhibitory receptor upon ligand induced tyrosine phosphorylation by recruiting cytoplasmic phosphatase(s) via their SH2 domain(s) that block signal transduction through dephosphorylation of signaling molecules. Induces apoptosis in acute myeloid leukemia (in vitro).
Targeted by drugs (based on IPA annotation)
  • arsenic trioxide/gemtuzumab ozogamicin/tretinoin
  • gemtuzumab ozogamicin
Biomarker applications (based on IPA annotation)
  • efficacy

All locus annotations are based on the sentinel SNP (rs12459419) and 5 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
  • CD33 CD33 molecule
Potentially regulated genes
  • SIGLEC12 sialic acid binding Ig-like lectin 12 (gene/pseudogene)
eQTL genes
  • SIGLECL1 SIGLEC family like 1
  • SIGLEC22P sialic acid binding Ig-like lectin 22, pseudogene
  • CD33 CD33 molecule

 

Results from other genome-wide association studies

Trait P Study Source
Alzheimer's disease 1.6×10-9 21460840 (PMID) GRASP2 nonQTL
Late onset Alzheimer's disease 1.6×10-9 21460841 (PMID) GRASP2 nonQTL
Alzheimer's disease (late onset) 2×10-9 21460841 (PMID) GWAS Catalog via SNiPA
P20138 protein abundance levels 5.1×10-9 22595970 (PMID) GRASP2 pQTL

Changes in CD33 protein levels co-associate with AD.

This locus harbours a replicated cis-pQTL with Myeloid cell surface antigen CD33 (CD33, aka Siglec-3). This SNP is an A14V amino acid exchange and in near-perfect LD with rs3865444. rs3865444 is an Alzheimer's disease risk variant [PubMed]. Increased expression of CD33 mRNA was associated with increasing AD pathology in temporal cortex brain samples [PubMed]. Here we show that also protein levels of CD33 associate with rs3865444. See the role of inflammation in Alzheimer's disease in Heppner et al. [PubMed]. See also Hernández-Caselles et al. [PubMed] for alternative splicing in CD33. See Chouraki and Seshadri [PubMed] for the genetics of Alzheimer's.

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.