Meta-GWAS of PCSK9 levels detects two novel loci at APOB and TM6SF2.
Meta-GWAS of PCSK9 levels detects two novel loci at APOB and TM6SF2.
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DOI：
10.1093/hmg/ddab279
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发表时间：
2022-03-21
影响因子：
3.5
通讯作者：
Scholz M
中科院分区：
文献类型：
--
作者：
Pott J;Gådin JR;Theusch E;Kleber ME;Delgado GE;Kirsten H;Hauck SM;Burkhardt R;Scharnagl H;Krauss RM;Loeffler M;März W;Thiery J;Silveira A;Van't Hooft FM;Scholz M
蛋白转化酶枯草杆菌素/酮素9型（PCSK9）在脂质代谢中起关键作用，因为它可以降解肝细胞膜上的低密度脂蛋白（LDL）受体。到目前为止，仅发现PCSK9基因位点的变异与PCSK9水平相关。在这里，我们旨在确定调节PCSK9水平的新基因位点及其与其他脂质性状的关系。此外，我们研究了PCSK9对冠状动脉疾病（CAD）的因果效应在多大程度上是由低密度脂蛋白-胆固醇（LDL-C）介导的。我们对多达12721个欧洲血统样本的PCSK9水平进行了全基因组关联研究荟萃分析。估计遗传率为10.3%，仅使用未接受他汀类药物治疗的患者样本，遗传率增加到12.6%。我们成功地复制了由三个独立信号组成的已知PCSK9序列。有趣的是，在一项对300名非裔美国人的研究中，我们证实了PCSK9基因座的不同变体。除了PCSK9，我们的荟萃分析还发现了三个具有全基因组意义的新位点。通过对顺式- eqtl和脂质性状的共定位分析，发现了其中两个生物学上合理的候选基因：APOB和TM6SF2。在双变量孟德尔随机化分析中，我们发现PCSK9对LDL-C有很强的影响，反之则没有。LDL-C介导PCSK9对CAD的总因果效应的63%。我们的研究发现了影响PCSK9水平的新的候选基因位点。PCSK9基因座本身存在种族异质性。虽然PCSK9对CAD的因果作用主要由LDL-C介导，但也存在独立的直接作用。
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key player in lipid metabolism, as it degrades low-density lipoprotein (LDL) receptors from hepatic cell membranes. So far, only variants of the PCSK9 gene locus were found to be associated with PCSK9 levels. Here we aimed to identify novel genetic loci that regulate PCSK9 levels and how they relate to other lipid traits. Additionally, we investigated to what extend the causal effect of PCSK9 on coronary artery disease (CAD) is mediated by low-density lipoprotein–cholesterol (LDL–C). We performed a genome-wide association study meta-analysis of PCSK9 levels in up to 12 721 samples of European ancestry. The estimated heritability was 10.3%, which increased to 12.6% using only samples from patients without statin treatment. We successfully replicated the known PCSK9 hit consisting of three independent signals. Interestingly, in a study of 300 African Americans, we confirmed the locus with a different PCSK9 variant. Beyond PCSK9, our meta-analysis detected three novel loci with genome-wide significance. Co-localization analysis with cis-eQTLs and lipid traits revealed biologically plausible candidate genes at two of them: APOB and TM6SF2. In a bivariate Mendelian Randomization analysis, we detected a strong effect of PCSK9 on LDL-C, but not vice versa. LDL-C mediated 63% of the total causal effect of PCSK9 on CAD. Our study identified novel genetic loci with plausible candidate genes affecting PCSK9 levels. Ethnic heterogeneity was observed at the PCSK9 locus itself. Although the causal effect of PCSK9 on CAD is mainly mediated by LDL-C, an independent direct effect also occurs.
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影响因子：
17.1
作者：
Finan C;Gaulton A;Kruger FA;Lumbers RT;Shah T;Engmann J;Galver L;Kelley R;Karlsson A;Santos R;Overington JP;Hingorani AD;Casas JP
通讯作者：
Casas JP
遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
影响因子：
14.9
作者：
Buniello, Annalisa;MacArthur, Jacqueline A. L.;Parkinson, Helen
通讯作者：
Parkinson, Helen
影响因子：
30.8
作者：
Holmen OL;Zhang H;Fan Y;Hovelson DH;Schmidt EM;Zhou W;Guo Y;Zhang J;Langhammer A;Løchen ML;Ganesh SK;Vatten L;Skorpen F;Dalen H;Zhang J;Pennathur S;Chen J;Platou C;Mathiesen EB;Wilsgaard T;Njølstad I;Boehnke M;Chen YE;Abecasis GR;Hveem K;Willer CJ
通讯作者：
Willer CJ
DOI：
10.1161/atvbaha.111.240549
发表时间：
2012-06-01
影响因子：
8.7
作者：
Chernogubova, Ekaterina;Strawbridge, Rona;van 't Hooft, Ferdinand M.
通讯作者：
van 't Hooft, Ferdinand M.