Bivariate genome-wide association study identifies novel pleiotropic loci for lipids and inflammation.
Bivariate genome-wide association study identifies novel pleiotropic loci for lipids and inflammation.
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DOI：
10.1186/s12864-016-2712-4
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发表时间：
2016-06-10
期刊：
影响因子：
4.4
通讯作者：
Dehghan A
中科院分区：
文献类型：
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作者：
Ligthart S;Vaez A;Hsu YH;Inflammation Working Group of the CHARGE Consortium;PMI-WG-XCP;LifeLines Cohort Study;Stolk R;Uitterlinden AG;Hofman A;Alizadeh BZ;Franco OH;Dehghan A
全基因组关联研究（GWAS）已经确定了C反应蛋白（CRP）和脂质的多个遗传位点，其中一些重叠。我们的目的是确定CRP和脂质之间的遗传多效性，以更好地了解慢性炎症和脂质代谢的共同生物学。在一个双变量GWAS中，我们使用经验加权线性组合检验统计量，合并了已发表的GWAS对CRP（n = 66，185）和血脂（包括LDL-胆固醇、HDL-胆固醇、甘油三酯和总胆固醇）（n = 100，184）的汇总统计量。我们在17，743名基因分型个体的独立样本中寻求新CRP相关性的复制，并在93，982名个体中进行了新脂质变体的计算机复制。在CRP和脂质中鉴定了50个潜在的多效性SNP：21个用于LDL-胆固醇和CRP，20个用于HDL-胆固醇和CRP，21个用于甘油三酯和CRP，20个用于总胆固醇和CRP。我们发现并显著复制了CTSB/FDFT 1（rs 10435719，Preplication：2.6 × 10−5），STAG 1/PCCB（rs7621025，Preplication：1.4 × 10−3）和FTO（rs 1558902，Preplication：2.7 × 10−5）或其附近的三种新的CRP SNP。在全球脂质遗传学联盟的代谢芯片样品的独立组中复制了七个多效性脂质基因座。注释复制的CRP SNP对附近基因表达的影响，我们观察到rs 10435719对FDFT 1基因表达的影响，以及rs7621025对PCCB的影响。我们的大规模联合GWAS分析确定了CRP和脂质的许多多效性位点，为脂质和炎症之间的遗传相互关系提供了进一步的见解。此外，我们还提供了FDFT 1、PCCB和FTO与CRP水平相关的证据。本文的在线版本（doi：10.1186/s12864-016-2712-4）包含补充材料，可供授权用户使用。
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. The online version of this article (doi:10.1186/s12864-016-2712-4) contains supplementary material, which is available to authorized users.