Bivariate genome-wide association study identifies novel pleiotropic loci for lipids and inflammation.
Genome-wide association studies (GWAS) have identified multiple genetic loci for C-reactive protein (CRP) and lipids, of which some overlap. We aimed to identify genetic pleiotropy among CRP and lipids in order to better understand the shared biology of chronic inflammation and lipid metabolism.



In a bivariate GWAS, we combined summary statistics of published GWAS on CRP (n = 66,185) and lipids, including LDL-cholesterol, HDL-cholesterol, triglycerides, and total cholesterol (n = 100,184), using an empirical weighted linear-combined test statistic. We sought replication for novel CRP associations in an independent sample of 17,743 genotyped individuals, and performed in silico replication of novel lipid variants in 93,982 individuals. Fifty potentially pleiotropic SNPs were identified among CRP and lipids: 21 for LDL-cholesterol and CRP, 20 for HDL-cholesterol and CRP, 21 for triglycerides, and CRP and 20 for total cholesterol and CRP. We identified and significantly replicated three novel SNPs for CRP in or near CTSB/FDFT1 (rs10435719, Preplication: 2.6 × 10(-5)), STAG1/PCCB (rs7621025, Preplication: 1.4 × 10(-3)) and FTO (rs1558902, Preplication: 2.7 × 10(-5)). Seven pleiotropic lipid loci were replicated in the independent set of MetaboChip samples of the Global Lipids Genetics Consortium. Annotating the effect of replicated CRP SNPs to the expression of nearby genes, we observed an effect of rs10435719 on gene expression of FDFT1, and an effect of rs7621025 on PCCB.



Our large scale combined GWAS analysis identified numerous pleiotropic loci for CRP and lipids providing further insight in the genetic interrelation between lipids and inflammation. In addition, we provide evidence for FDFT1, PCCB and FTO to be associated with CRP levels.
Department of Epidemiology, Erasmus University Medical Center, PO Box 2040, 3000CA, Rotterdam, The Netherlands.
Symen
S
Ligthart
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Ahmad
A
Vaez
Hebrew SeniorLife Institute for Aging Research and Harvard Medical School, Boston, MA, USA.|Molecular and Integrative Physiological Sciences Program, Harvard School of Public Health, Boston, MA, USA.|Framingham Heart Study, Framingham, MA, USA.
Yi-Hsiang
YH
Hsu
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Ronald
R
Stolk
Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
André G
AG
Uitterlinden
Department of Epidemiology, Erasmus University Medical Center, PO Box 2040, 3000CA, Rotterdam, The Netherlands.
Albert
A
Hofman
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Behrooz Z
BZ
Alizadeh
Department of Epidemiology, Erasmus University Medical Center, PO Box 2040, 3000CA, Rotterdam, The Netherlands.
Oscar H
OH
Franco
Department of Epidemiology, Erasmus University Medical Center, PO Box 2040, 3000CA, Rotterdam, The Netherlands. a.dehghan@erasmusmc.nl.
Abbas
A
Dehghan
D015415:Biomarkers; D002097:C-Reactive Protein; D008076:Cholesterol, HDL; D004261:DNA Replication; D015870:Gene Expression; D056726:Genetic Association Studies; D055106:Genome-Wide Association Study; D007249:Inflammation / Q000235:genetics*; D050356:Lipid Metabolism / Q000235:genetics*; D020412:Multifactorial Inheritance; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D014280:Triglycerides
D015415:Biomarkers; D008076:Cholesterol, HDL; D014280:Triglycerides; D002097:C-Reactive Protein
C-reactive protein; Genetic pleiotropy; Genome-wide association study; Inflammation; Lipids