In Silico Post Genome-Wide Association Studies Analysis of C-Reactive Protein Loci Suggests an Important Role for Interferons.
BACKGROUND
Genome-wide association studies (GWASs) have successfully identified several single nucleotide polymorphisms (SNPs) associated with serum levels of C-reactive protein (CRP). An important limitation of GWASs is that the identified variants merely flag the nearby genomic region and do not necessarily provide a direct link to the biological mechanisms underlying their corresponding phenotype. Here we apply a bioinformatics-based approach to uncover the functional characteristics of the 18 SNPs that had previously been associated with CRP at a genome-wide significant level.


RESULTS
In the first phase of in silico sequencing, we explore the vicinity of GWAS SNPs to identify all linked variants. In the second phase of expression quantitative trait loci analysis, we attempt to identify all nearby genes whose expression levels are associated with the corresponding GWAS SNPs. These 2 phases generate several relevant genes that serve as input to the next phase of functional network analysis. Our in silico sequencing analysis using 1000 Genomes Project data identified 7 nonsynonymous SNPs, which are in moderate to high linkage disequilibrium (r(2)>0.5) with the GWAS SNPs. Our expression quantitative trait loci analysis, which was based on one of the largest single data sets of genome-wide expression probes (n>5000) identified 23 significantly associated expression probes belonging to 15 genes (false discovery rate <0.01). The final phase of functional network analysis revealed 93 significantly enriched biological processes (false discovery rate <0.01).


CONCLUSIONS
Our post-GWAS analysis of CRP GWAS SNPs confirmed the previously known overlap between CRP and lipids biology. Additionally, it suggested an important role for interferons in the metabolism of CRP.
From the Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen (A.V., B.P.P., I.M.N., H.S., B.Z.A.); Department of Psychiatry, VU University Medical Center, Amsterdam (R.J., B.W.J.H.P.); and Neuroscience Campus Amsterdam, VU University and VU University Medical Center, Amsterdam (R.J., J.-J.H., E.J.C.d.G., D.I.B., B.W.J.H.P.), EMGO+ Institute, VU University and VU University Medical Center, Amsterdam (J.-J.H., E.J.C.d.G., D.I.B., B.W.J.H.P.), Department of Biological Psychology, VU University, Amsterdam, the Netherlands (J.-J.H., E.J.C.d.G., D.I.B.); and School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran (A.V.). b.z.alizadeh@umcg.nl a.vaez@umcg.nl.
Ahmad
A
Vaez
From the Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen (A.V., B.P.P., I.M.N., H.S., B.Z.A.); Department of Psychiatry, VU University Medical Center, Amsterdam (R.J., B.W.J.H.P.); and Neuroscience Campus Amsterdam, VU University and VU University Medical Center, Amsterdam (R.J., J.-J.H., E.J.C.d.G., D.I.B., B.W.J.H.P.), EMGO+ Institute, VU University and VU University Medical Center, Amsterdam (J.-J.H., E.J.C.d.G., D.I.B., B.W.J.H.P.), Department of Biological Psychology, VU University, Amsterdam, the Netherlands (J.-J.H., E.J.C.d.G., D.I.B.); and School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran (A.V.).
Rick
R
Jansen
From the Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen (A.V., B.P.P., I.M.N., H.S., B.Z.A.); Department of Psychiatry, VU University Medical Center, Amsterdam (R.J., B.W.J.H.P.); and Neuroscience Campus Amsterdam, VU University and VU University Medical Center, Amsterdam (R.J., J.-J.H., E.J.C.d.G., D.I.B., B.W.J.H.P.), EMGO+ Institute, VU University and VU University Medical Center, Amsterdam (J.-J.H., E.J.C.d.G., D.I.B., B.W.J.H.P.), Department of Biological Psychology, VU University, Amsterdam, the Netherlands (J.-J.H., E.J.C.d.G., D.I.B.); and School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran (A.V.).
Bram P
BP
Prins
From the Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen (A.V., B.P.P., I.M.N., H.S., B.Z.A.); Department of Psychiatry, VU University Medical Center, Amsterdam (R.J., B.W.J.H.P.); and Neuroscience Campus Amsterdam, VU University and VU University Medical Center, Amsterdam (R.J., J.-J.H., E.J.C.d.G., D.I.B., B.W.J.H.P.), EMGO+ Institute, VU University and VU University Medical Center, Amsterdam (J.-J.H., E.J.C.d.G., D.I.B., B.W.J.H.P.), Department of Biological Psychology, VU University, Amsterdam, the Netherlands (J.-J.H., E.J.C.d.G., D.I.B.); and School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran (A.V.).
Jouke-Jan
JJ
Hottenga
From the Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen (A.V., B.P.P., I.M.N., H.S., B.Z.A.); Department of Psychiatry, VU University Medical Center, Amsterdam (R.J., B.W.J.H.P.); and Neuroscience Campus Amsterdam, VU University and VU University Medical Center, Amsterdam (R.J., J.-J.H., E.J.C.d.G., D.I.B., B.W.J.H.P.), EMGO+ Institute, VU University and VU University Medical Center, Amsterdam (J.-J.H., E.J.C.d.G., D.I.B., B.W.J.H.P.), Department of Biological Psychology, VU University, Amsterdam, the Netherlands (J.-J.H., E.J.C.d.G., D.I.B.); and School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran (A.V.).
Eco J C
EJ
de Geus
From the Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen (A.V., B.P.P., I.M.N., H.S., B.Z.A.); Department of Psychiatry, VU University Medical Center, Amsterdam (R.J., B.W.J.H.P.); and Neuroscience Campus Amsterdam, VU University and VU University Medical Center, Amsterdam (R.J., J.-J.H., E.J.C.d.G., D.I.B., B.W.J.H.P.), EMGO+ Institute, VU University and VU University Medical Center, Amsterdam (J.-J.H., E.J.C.d.G., D.I.B., B.W.J.H.P.), Department of Biological Psychology, VU University, Amsterdam, the Netherlands (J.-J.H., E.J.C.d.G., D.I.B.); and School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran (A.V.).
Dorret I
DI
Boomsma
From the Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen (A.V., B.P.P., I.M.N., H.S., B.Z.A.); Department of Psychiatry, VU University Medical Center, Amsterdam (R.J., B.W.J.H.P.); and Neuroscience Campus Amsterdam, VU University and VU University Medical Center, Amsterdam (R.J., J.-J.H., E.J.C.d.G., D.I.B., B.W.J.H.P.), EMGO+ Institute, VU University and VU University Medical Center, Amsterdam (J.-J.H., E.J.C.d.G., D.I.B., B.W.J.H.P.), Department of Biological Psychology, VU University, Amsterdam, the Netherlands (J.-J.H., E.J.C.d.G., D.I.B.); and School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran (A.V.).
Brenda W J H
BW
Penninx
From the Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen (A.V., B.P.P., I.M.N., H.S., B.Z.A.); Department of Psychiatry, VU University Medical Center, Amsterdam (R.J., B.W.J.H.P.); and Neuroscience Campus Amsterdam, VU University and VU University Medical Center, Amsterdam (R.J., J.-J.H., E.J.C.d.G., D.I.B., B.W.J.H.P.), EMGO+ Institute, VU University and VU University Medical Center, Amsterdam (J.-J.H., E.J.C.d.G., D.I.B., B.W.J.H.P.), Department of Biological Psychology, VU University, Amsterdam, the Netherlands (J.-J.H., E.J.C.d.G., D.I.B.); and School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran (A.V.).
Ilja M
IM
Nolte
From the Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen (A.V., B.P.P., I.M.N., H.S., B.Z.A.); Department of Psychiatry, VU University Medical Center, Amsterdam (R.J., B.W.J.H.P.); and Neuroscience Campus Amsterdam, VU University and VU University Medical Center, Amsterdam (R.J., J.-J.H., E.J.C.d.G., D.I.B., B.W.J.H.P.), EMGO+ Institute, VU University and VU University Medical Center, Amsterdam (J.-J.H., E.J.C.d.G., D.I.B., B.W.J.H.P.), Department of Biological Psychology, VU University, Amsterdam, the Netherlands (J.-J.H., E.J.C.d.G., D.I.B.); and School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran (A.V.).
Harold
H
Snieder
From the Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen (A.V., B.P.P., I.M.N., H.S., B.Z.A.); Department of Psychiatry, VU University Medical Center, Amsterdam (R.J., B.W.J.H.P.); and Neuroscience Campus Amsterdam, VU University and VU University Medical Center, Amsterdam (R.J., J.-J.H., E.J.C.d.G., D.I.B., B.W.J.H.P.), EMGO+ Institute, VU University and VU University Medical Center, Amsterdam (J.-J.H., E.J.C.d.G., D.I.B., B.W.J.H.P.), Department of Biological Psychology, VU University, Amsterdam, the Netherlands (J.-J.H., E.J.C.d.G., D.I.B.); and School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran (A.V.). b.z.alizadeh@umcg.nl a.vaez@umcg.nl.
Behrooz Z
BZ
Alizadeh
D000483:Alleles; D002097:C-Reactive Protein / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007372:Interferons / Q000378:metabolism*; D015810:Linkage Disequilibrium; D008137:Longitudinal Studies; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D017422:Sequence Analysis, DNA
D002097:C-Reactive Protein; D007372:Interferons
C-reactive protein; genome wide association study; interferon