HelmholtzZentrum munich
WCMC

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

ONLINE SUPPLEMENTARY INFORMATION

Ideogram
Proteome annotation
Locus annotations

Locus 208

Top associations per target

Target cis/​trans Study SNP SNP location Maj/​min allele MAF N βinv seinv Pinv fclog Plog Praw
SIRT2 trans Discovery rs1801689 17:64,210,580 A/C 0.03 996 1.132 0.124 2.8×10-19 1.330 1.4×10-9 0.095
Dkk-4 trans Discovery rs1801689 17:64,210,580 A/C 0.03 996 0.722 0.116 7×10-10 1.190 8.4×10-10 7.1×10-9

 

Regional association plots

NAD-dependent protein deacetylase sirtuin-2 (SIRT2)

Dickkopf-related protein 4 (Dkk-4)

 

Boxplots and histograms for top associations

NAD-dependent protein deacetylase sirtuin-2 (SIRT2)

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

Dickkopf-related protein 4 (Dkk-4)

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

NAD-dependent protein deacetylase sirtuin-2 (SIRT2)

Target (abbrv.) SIRT2
Target (full name) NAD-dependent protein deacetylase sirtuin-2
Somalogic ID (Sequence ID) SL006629 (5030-52_1)
Entrez Gene Symbol SIRT2
UniProt ID Q8IXJ6
UniProt Comment
  • NAD-dependent protein deacetylase, which deacetylates internal lysines on histone and alpha-tubulin as well as many other proteins such as key transcription factors. Participates in the modulation of multiple and diverse biological processes such as cell cycle control, genomic integrity, microtubule dynamics, cell differentiation, metabolic networks, and autophagy. Plays a major role in the control of cell cycle progression and genomic stability. Functions in the antephase checkpoint preventing precocious mitotic entry in response to microtubule stress agents, and hence allowing proper inheritance of chromosomes. Positively regulates the anaphase promoting complex/cyclosome (APC/C) ubiquitin ligase complex activity by deacetylating CDC20 and FZR1, then allowing progression through mitosis. Associates both with chromatin at transcriptional start sites (TSSs) and enhancers of active genes. Plays a role in cell cycle and chromatin compaction through epigenetic modulation of the regulation of histone H4 'Lys-20' methylation (H4K20me1) during early mitosis. Specifically deacetylates histone H4 at 'Lys-16' (H4K16ac) between the G2/M transition and metaphase enabling H4K20me1 deposition by SETD8 leading to ulterior levels of H4K20me2 and H4K20me3 deposition throughout cell cycle, and mitotic S-phase progression. Deacetylates SETD8 modulating SETD8 chromatin localization during the mitotic stress response. Deacetylates also histone H3 at 'Lys-57' (H3K56ac) during the mitotic G2/M transition. Upon bacterium Listeria monocytogenes infection, deacetylates 'Lys-18' of histone H3 in a receptor tyrosine kinase MET- and PI3K/Akt-dependent manner, thereby inhibiting transcriptional activity and promoting late stages of listeria infection. During oocyte meiosis progression, may deacetylate histone H4 at 'Lys-16' (H4K16ac) and alpha-tubulin, regulating spindle assembly and chromosome alignment by influencing microtubule dynamics and kinetochore function. Deacetylates alpha-tubulin at 'Lys-40' and hence controls neuronal motility, oligodendroglial cell arbor projection processes and proliferation of non-neuronal cells. Phosphorylation at Ser-368 by a G1/S-specific cyclin E-CDK2 complex inactivates SIRT2-mediated alpha-tubulin deacetylation, negatively regulating cell adhesion, cell migration and neurite outgrowth during neuronal differentiation. Deacetylates PARD3 and participates in the regulation of Schwann cell peripheral myelination formation during early postnatal development and during postinjury remyelination. Involved in several cellular metabolic pathways. Plays a role in the regulation of blood glucose homeostasis by deacetylating and stabilizing phosphoenolpyruvate carboxykinase PCK1 activity in response to low nutrient availability. Acts as a key regulator in the pentose phosphate pathway (PPP) by deacetylating and activating the glucose-6-phosphate G6PD enzyme, and therefore, stimulates the production of cytosolic NADPH to counteract oxidative damage. Maintains energy homeostasis in response to nutrient deprivation as well as energy expenditure by inhibiting adipogenesis and promoting lipolysis. Attenuates adipocyte differentiation by deacetylating and promoting FOXO1 interaction to PPARG and subsequent repression of PPARG-dependent transcriptional activity. Plays a role in the regulation of lysosome-mediated degradation of protein aggregates by autophagy in neuronal cells. Deacetylates FOXO1 in response to oxidative stress or serum deprivation, thereby negatively regulating FOXO1-mediated autophagy. Deacetylates a broad range of transcription factors and co-regulators regulating target gene expression. Deacetylates transcriptional factor FOXO3 stimulating the ubiquitin ligase SCF(SKP2)-mediated FOXO3 ubiquitination and degradation. Deacetylates HIF1A and therefore promotes HIF1A degradation and inhibition of HIF1A transcriptional activity in tumor cells in response to hypoxia. Deacetylates RELA in the cytoplasm inhibiting NF-kappaB-dependent transcription activation upon TNF-alpha stimulation. Inhibits transcriptional activation by deacetylating p53/TP53 and EP300. Deacetylates also EIF5A. Functions as a negative regulator on oxidative stress-tolerance in response to anoxia-reoxygenation conditions. Plays a role as tumor suppressor.
Pathway Interaction Database
  • Signaling events mediated by HDAC Class I
  • Signaling events mediated by HDAC Class III

Dickkopf-related protein 4 (Dkk-4)

Target (abbrv.) Dkk-4
Target (full name) Dickkopf-related protein 4
Somalogic ID (Sequence ID) SL010612 (3365-7_2)
Entrez Gene Symbol DKK4
UniProt ID Q9UBT3
UniProt Comment
  • Antagonizes canonical Wnt signaling by inhibiting LRP5/6 interaction with Wnt and by forming a ternary complex with the transmembrane protein KREMEN that promotes internalization of LRP5/6. DKKs play an important role in vertebrate development, where they locally inhibit Wnt regulated processes such as antero-posterior axial patterning, limb development, somitogenesis and eye formation. In the adult, Dkks are implicated in bone formation and bone disease, cancer and Alzheimer disease (By similarity).
Pathway Interaction Database
  • Regulation of nuclear beta catenin signaling and target gene transcription
Reactome
  • TCF dependent signaling in response to WNT
  • misspliced LRP5 mutants have enhanced beta-catenin-dependent signaling
  • negative regulation of TCF-dependent signaling by WNT ligand antagonists

All locus annotations are based on the sentinel SNP (rs1801689) and 4 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
  • PSMD7P1 proteasome (prosome, macropain) 26S subunit, non-ATPase, 7 pseudogene 1
  • APOH apolipoprotein H (beta-2-glycoprotein I)
  • PRKCA protein kinase C, alpha

 

Results from other genome-wide association studies

Trait P Study Source
LDL cholesterol 9.4×10-14 23063622 (PMID) GRASP2 nonQTL
Total cholesterol 4.9×10-6 23063622 (PMID) GRASP2 nonQTL
Triglycerides 3.4×10-5 24097068 (PMID) Supplemental file