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

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Locus annotations

Locus 71

Top associations per target

Target cis/​trans Study SNP SNP location Maj/​min allele MAF N βinv seinv Pinv fclog Plog Praw
GRN trans Discovery rs646776 1:109,818,530 T/C 0.22 996 -0.758 0.047 1×10-52 -1.120 2.3×10-52 2.4×10-47
GRN trans Replication rs646776 1:109,818,530 A/G 0.20 337 -0.674 0.072 1.7×10-18 -1.150 9.7×10-15 1.2×10-11
Catalase trans Discovery rs646776 1:109,818,530 T/C 0.22 996 -0.336 0.049 1.5×10-11 -1.090 6.8×10-10 5.1×10-7
Catalase trans Replication rs660240 1:109,817,838 G/A 0.20 337 -0.057 0.089 0.527 -1.010 0.702 0.924
RGMA trans Discovery rs646776 1:109,818,530 T/C 0.22 996 -0.324 0.052 5.1×10-10 -1.060 1.3×10-9 7.8×10-9
RGMA trans Replication rs629301 1:109,818,306 A/C 0.20 337 -0.155 0.067 0.022 -1.040 0.048 0.024

 

Regional association plots

 

Boxplots and histograms for top associations

Granulins (GRN)

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

Catalase

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

Repulsive guidance molecule A (RGMA)

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

Granulins (GRN)

Target (abbrv.) GRN
Target (full name) Granulins
Somalogic ID (Sequence ID) SL007173 (4992-49_1)
Entrez Gene Symbol GRN
UniProt ID P28799
UniProt Comment
  • Granulins have possible cytokine-like activity. They may play a role in inflammation, wound repair, and tissue remodeling.
Wiki Pathways
  • Integrated Breast Cancer Pathway

Catalase

Target (abbrv.) Catalase
Target (full name) Catalase
Somalogic ID (Sequence ID) SL000342 (3488-64_2)
Entrez Gene Symbol CAT
UniProt ID P04040
UniProt Comment
  • Occurs in almost all aerobically respiring organisms and serves to protect cells from the toxic effects of hydrogen peroxide. Promotes growth of cells including T-cells, B-cells, myeloid leukemia cells, melanoma cells, mastocytoma cells and normal and transformed fibroblast cells.
Targeted by drugs (based on IPA annotation)
  • fomepizole
Biomarker applications (based on IPA annotation)
  • diagnosis
Wiki Pathways
  • DNA damage response (only ATM dependent)
  • Folate Metabolism
  • Oxidative Stress
  • Selenium Pathway
  • Tryptophan metabolism
Pathway Interaction Database
  • FoxO family signaling
Reactome
  • Detoxification of Reactive Oxygen Species
  • Purine catabolism
Pathway Studio
  • Peroxisome Protein Import and Peroxisome Division

Repulsive guidance molecule A (RGMA)

Target (abbrv.) RGMA
Target (full name) Repulsive guidance molecule A
Somalogic ID (Sequence ID) SL010467 (3833-10_2)
Entrez Gene Symbol RGMA
UniProt ID Q96B86
UniProt Comment
  • Member of the repulsive guidance molecule (RGM) family that performs several functions in the developing and adult nervous system. Regulates cephalic neural tube closure, inhibits neurite outgrowth and cortical neuron branching, and the formation of mature synapses. Binding to its receptor NEO1/neogenin induces activation of RHOA-ROCK1/Rho-kinase signaling pathway through UNC5B-ARHGEF12/LARG-PTK2/FAK1 cascade, leading to collapse of the neuronal growth cone and neurite outgrowth inhibition. Furthermore, RGMA binding to NEO1/neogenin leads to HRAS inactivation by influencing HRAS-PTK2/FAK1-AKT1 pathway. It also functions as a bone morphogenetic protein (BMP) coreceptor that may signal through SMAD1, SMAD5, and SMAD8.

All locus annotations are based on the sentinel SNP (rs646776) and 9 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
  • PSRC1 proline/serine-rich coiled-coil 1
  • CELSR2 cadherin, EGF LAG seven-pass G-type receptor 2
Potentially regulated genes
  • AMPD2 adenosine monophosphate deaminase 2
eQTL genes
  • SORT1 sortilin 1
  • PSRC1 proline/serine-rich coiled-coil 1
  • CELSR2 cadherin, EGF LAG seven-pass G-type receptor 2

 

Results from other genome-wide association studies

Trait P Study Source
SORT1 gene expression in human liver 2×10-300 20686565 (PMID) GRASP2 nonQTL
LDL cholesterol 1.6×10-272 24097068 (PMID) Supplemental file
PSRC1 gene expression in human liver 2×10-271 20686565 (PMID) GRASP2 nonQTL
Gene expression of SORT1 in Liver 3.8×10-227 21378990 (PMID) GRASP2 nonQTL
Gene expression of PSRC1 in Liver 1.4×10-193 21378990 (PMID) GRASP2 nonQTL
Triglycerides 4.8×10-187 24097068 (PMID) Supplemental file
Cholesterol, total 2×10-170 24097068 (PMID) GWAS Catalog via SNiPA
Gene expression of reporter ID 10026392691 in liver 7.2×10-140 20084173 (PMID) GRASP2 eQTL
Gene expression of reporter ID 10023814496 in liver 1.3×10-137 20084173 (PMID) GRASP2 eQTL
Gene expression of reporter ID 10023846331 in liver 3.2×10-137 20084173 (PMID) GRASP2 eQTL
Total cholesterol 3.2×10-137 20686565 (PMID) GRASP2 nonQTL
CELSR2 gene expression in human liver 5×10-94 20686565 (PMID) GRASP2 nonQTL
SORT1 gene expression in liver tissue 5.2×10-88 21602305 (PMID) GRASP2 eQTL
Gene expression of SORT1 in liver 1.4×10-87 21637794 (PMID) GRASP2 eQTL
PSRC1 gene expression in liver tissue 3.1×10-86 21602305 (PMID) GRASP2 eQTL
Gene expression of CELSR2 in Liver 5×10-73 21378990 (PMID) GRASP2 nonQTL
CELSR2 gene expression in liver tissue 6.3×10-68 21602305 (PMID) GRASP2 eQTL
Gene expression of PSRC1 in peripheral blood monocytes 2.3×10-56 20502693 (PMID) GRASP2 eQTL
APOB assay lipoprotein fraction concentration 1.8×10-53 19936222 (PMID) GRASP2 nonQTL
Lipid metabolism phenotypes 2×10-53 19936222 (PMID) GWAS Catalog via SNiPA
Gene expression of PSRC1 in liver 2.2×10-53 18462017 (PMID) GRASP2 eQTL
LDL cholesterol lipoprotein fraction concentration 5×10-46 19936222 (PMID) GRASP2 nonQTL
APOB (apolipoprotein B) 3.9×10-41 23100282 (PMID) GRASP2 nonQTL
cg09754932 (chr1:109820547) 2.4×10-40 10.1101/033084 (DOI) BIOS QTL cis-meQTLs
APOB assay lipoprotein fraction concentration in fasting sample 3.7×10-39 19936222 (PMID) GRASP2 nonQTL
PSRC1 transcript levels 8.7×10-38 21606135 (PMID) GRASP2 nonQTL
LDL cholesterol in serum 1.2×10-33 18262040 (PMID) GRASP2 nonQTL
LDL cholesterol lipoprotein fraction concentration in fasting sample 1.2×10-32 19936222 (PMID) GRASP2 nonQTL
LDL cholesterol (female) 3.4×10-31 22629316 (PMID) GRASP2 nonQTL
Gene expression of PSRC1 in blood 7.3×10-31 21829388 (PMID) GRASP2 eQTL
Plasma progranulin levels 1.7×10-30 21087763 (PMID) GRASP2 nonQTL
Progranulin levels 2×10-30 21087763 (PMID) GWAS Catalog via SNiPA
LDL cholesterol total lipoprotein fraction concentration 2.4×10-27 19936222 (PMID) GRASP2 nonQTL
Gene expression of PSRC1 in Blood 1.1×10-26 21378990 (PMID) GRASP2 nonQTL
Coronary artery disease (CAD) 4.7×10-26 23202125 (PMID) GRASP2 nonQTL
Coronary artery disease and myocardial infarction 4.7×10-26 23202125 (PMID) Supplemental file
LDL cholesterol (male) 6.3×10-25 22629316 (PMID) GRASP2 nonQTL
Gene expression of CELSR2 in liver 3.1×10-24 18462017 (PMID) GRASP2 eQTL
SYPL2 gene expression in human liver 1×10-23 20686565 (PMID) GRASP2 nonQTL
Lipoprotein-associated phospholipase A2 activity (Lp-PLA2) 1.5×10-22 23118302 (PMID) GRASP2 nonQTL
Cardiovascular disease risk factors 2×10-22 21943158 (PMID) GWAS Catalog via SNiPA
Lipoprotein-associated phospholipase A2 activity and mass 2×10-22 23118302 (PMID) GWAS Catalog via SNiPA
Gene expression of PSRC1 in Monocytes 7.7×10-21 21378990 (PMID) GRASP2 nonQTL
LDL cholesterol total lipoprotein fraction concentration in fasting sample 2.2×10-20 19936222 (PMID) GRASP2 nonQTL
Coronary artery disease (CAD) age <=50 2.8×10-20 23202125 (PMID) GRASP2 nonQTL
Gene expression of PSRC1 in Macrophages 4.8×10-20 21378990 (PMID) GRASP2 nonQTL
Metabolite levels 2×10-19 21909109 (PMID) GWAS Catalog via SNiPA
VLDL cholesterol small lipoprotein fraction concentration 6.3×10-19 19936222 (PMID) GRASP2 nonQTL
Coronary artery disease (CAD) (males) 1.3×10-18 23202125 (PMID) GRASP2 nonQTL
Lp-PLA2 activity 1.3×10-17 22003152 (PMID) GRASP2 nonQTL
Coronary artery disease or large artery stroke 8×10-17 24262325 (PMID) GWAS Catalog via SNiPA
PSMA5 gene expression in human liver 9×10-17 20686565 (PMID) GRASP2 nonQTL
"Gene expression of CELSR2 [transcript NM_001408, probe A_24_P182620] in liver" 2×10-16 21637794 (PMID) GRASP2 eQTL
Coronary artery disease (CAD) with myocardial infarction (MI) 2.2×10-16 23202125 (PMID) GRASP2 nonQTL
Metabolic syndrome domains (Atherogenic Dyslipidemia - PC1) 8×10-16 22022282 (PMID) GRASP2 nonQTL
HDL cholesterol 1.7×10-15 24097068 (PMID) Supplemental file
VLDL cholesterol small lipoprotein fraction concentration in fasting sample 1.6×10-13 19936222 (PMID) GRASP2 nonQTL
Metabolic syndrome domains (Multivariate analysis) 3.6×10-13 22022282 (PMID) GRASP2 nonQTL
LDL cholesterol (mmol/l) 6.6×10-13 19060910 (PMID) GRASP2 nonQTL
Lipoproteins, ldl 2.2×10-12 pha002902 (dbGaP) dbGaP via SNiPA
Serum M-LDL-C/M-LDL-PL 2.4×10-12 22286219 (PMID) GRASP2 metabQTL
LDL cholesterol exam 1 values 6.2×10-12 19060906 (PMID) GRASP2 nonQTL
Myocardial infarction (MI) early age of onset 7.9×10-12 19198609 (PMID) GRASP2 nonQTL
Coronary heart disease (CHD) 8×10-12 21347282 (PMID) GRASP2 nonQTL
Myocardial infarction (early onset) 8×10-12 19198609 (PMID) GWAS Catalog via SNiPA
Serum Gp/Tot-C 8.9×10-12 22286219 (PMID) GRASP2 metabQTL
LDL cholesterol small lipoprotein fraction concentration 9.2×10-12 19936222 (PMID) GRASP2 nonQTL
Serum L-LDL-FC 6.9×10-11 22286219 (PMID) GRASP2 metabQTL
VLDL cholesterol total lipoprotein fraction concentration 7.1×10-11 19936222 (PMID) GRASP2 nonQTL
Angiographic coronary artery disease (CAD) 7.9×10-11 21239051 (PMID) GRASP2 nonQTL
Coronary Artery Disease 8×10-11 21239051 (PMID) GWAS Catalog via SNiPA
Total cholesterol (exam 1) 9.2×10-11 19060906 (PMID) GRASP2 nonQTL
Coronary heart disease 3×10-10 21378990 (PMID) GWAS Catalog via SNiPA
Gene expression of PSRC1 in Subcutaneous adipose 1.3×10-9 21378990 (PMID) GRASP2 nonQTL
LDL cholesterol small lipoprotein fraction concentration in fasting sample 5×10-9 19936222 (PMID) GRASP2 nonQTL
cholesterol 5×10-9 24816252 (PMID) gwas.eu via SNiPA
LDL cholesterol large lipoprotein fraction concentration 6×10-9 19936222 (PMID) GRASP2 nonQTL
Coronary artery disease or ischemic stroke 1×10-8 24262325 (PMID) GWAS Catalog via SNiPA
Coronary artery disease (CAD) with age of onset <=50 1.1×10-8 21378990 (PMID) GRASP2 nonQTL
LDL cholesterol change with statins 3.7×10-8 20339536 (PMID) GRASP2 nonQTL
Height 3.8×10-8 25282103 (PMID) Supplemental file
Myocardial infarction (MI) 4.3×10-8 21378990 (PMID) GRASP2 nonQTL
Coronary artery disease (CAD) age >50 5×10-8 23202125 (PMID) GRASP2 nonQTL
LDL cholesterol (baseline) 5×10-8 21977987 (PMID) GRASP2 nonQTL
Coronary heart disease (CHD) or coronary artery disease (CAD) 6.5×10-8 22003152 (PMID) GRASP2 nonQTL
APOB (apolipoprotein B) response after 40mg daily simvastatin treatment 2.4×10-7 23100282 (PMID) GRASP2 nonQTL
Gene expression of PSMA5 in liver 2.4×10-7 18462017 (PMID) GRASP2 eQTL
Coronary artery disease (CAD) (men) 5.7×10-7 21378990 (PMID) GRASP2 nonQTL
Gene expression of KIAA1324 in blood 1.7×10-6 21829388 (PMID) GRASP2 eQTL
Total cholesterol to HDL cholesterol ratio 1.8×10-6 19060906 (PMID) GRASP2 nonQTL
Gene expression of PSRC1 [probe 201896_s_at] in prefrontal cortex 2.6×10-6 20351726 (PMID) GRASP2 eQTL
Gene expression of PSRC1 (probeID ILMN_1671843) in temporal cortex in Alzheimer's disease cases and controls 3.3×10-6 22685416 (PMID) GRASP2 eQTL
Response to statin therapy 4×10-6 20339536 (PMID) GWAS Catalog via SNiPA
Total cholesterol change with statins 4.2×10-6 20339536 (PMID) GRASP2 nonQTL
Coronary artery disease (CAD) (women) 4.7×10-6 21378990 (PMID) GRASP2 nonQTL
Coronary artery disease (CAD) with age of onset >50 5.5×10-6 21378990 (PMID) GRASP2 nonQTL
Gene expression of CELSR2 in peripheral blood monocytes 7.6×10-6 20502693 (PMID) GRASP2 eQTL
Gene expression of SALL3 in blood 1×10-5 21829388 (PMID) GRASP2 eQTL
Coronary artery disease (CAD) by angiography 1.8×10-5 21378990 (PMID) GRASP2 nonQTL
Cholesterol 2.7×10-5 pha003078 (dbGaP) dbGaP via SNiPA
Coronary artery disease (CAD) (females) 3.4×10-5 23202125 (PMID) GRASP2 nonQTL
Gene expression of PSRC1 (probeID ILMN_1801152) in temporal cortex in Alzheimer's disease cases and controls 5.9×10-5 22685416 (PMID) GRASP2 eQTL
Lp-PLA2 mass 7.1×10-5 22003152 (PMID) GRASP2 nonQTL
Gene expression of PSRC1 (probeID ILMN_2315964) in temporal cortex in Alzheimer's disease cases and controls 8.1×10-5 22685416 (PMID) GRASP2 eQTL
LDL cholesterol response after 40mg daily simvastatin treatment 9.5×10-5 23100282 (PMID) GRASP2 nonQTL
Coronary artery calcification (CAC) 1.6×10-4 23727086 (PMID) GRASP2 nonQTL
Serum concentration of cholesterol 2.4×10-4 21886157 (PMID) GRASP2 metabQTL
Serum concentration of butyrylcarnitine 3×10-4 21886157 (PMID) GRASP2 metabQTL
Hip circumfence 3.8×10-4 25673412 (PMID) Supplemental file

A potential role for RGMA and CAT in coronary artery disease.

Trans-association of rs646776 replicates a strong immuno-assay based GWAS hit [PubMed] at the sortilin (SORT1) locus. Nguyen et al. [PubMed] state that "our understanding of the relationship between anti-inflammatory progranulin and its processing to the proinflammatory granulins remains limited" .. "in cultured macrophages, HDL blocked cleavage of progranulin into granulins and inhibited granulin-mediated inflammation" .. "Sortilin-deficient (Sort1 /) mice exhibited fivefold more circulating progranulin". In addition to the replicated GRN association we find here two weaker trans-associations of rs646776, with Catalase (CAT) and with Repulsive guidance molecule A (RGMA). The CAT association could not be replicated in QMDiab due to a lack of power, the RGMA association showed nominal association (p=0.022) with a similar trend (levels of all three proteins decrease with the minor allele of rs646776). Note that the SORT1 locus is also a major GWAS locus for total and LDL cholesterol, coronary artery disease. Although not replicated in QMDiab, our association data in KORA suggests a role for RGMA and CAT in the pathways that link cholesterol to coronary artery disease.

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.