Meta-GWAS of PCSK9 levels detects two novel loci atAPOBandTM6SF2

Abstract

Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key player in lipid metabolism, as it degrades 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 LDL-C. Methods & Results 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. Conclusion Our study identified novel genetic loci with plausible candidate genes affecting PCSK9 levels. Ethnic heterogeneity was observed at the PCSK9 locus itself. While the causal effect of PCSK9 on CAD is mainly mediated by LDL-C, an independent direct effect also occurs.

Genetic regulation of the human plasma proteome in 54,306 UK Biobank participants

“…For stroke, we found significant causal associations with increased risk of large artery ischaemic stroke subtype (MRlog(IS-LA OR)=0.27, p=0.011). Whilst genetic PCSK9 effects on LDL, total cholesterol and CHD have been found previously 36,75 , effects of PCSK9 on HDL cholesterol and large artery ischaemic stroke have not been substantiated by previous MR studies, likely due to decreased power. These findings extends the corroborated effects observed across multiple randomised clinical trials of PCSK9 inhibitors 72 .…”

Association of genetic polymorphisms of PCSK9 with type 2 diabetes in Uygur Chinese population

“…In the present study, we genotyped polymorphisms of four SNPs in the PCSK9 gene and found that rs2483205 and rs2495477 were associated with T2DM. Rs2495477 is located in the fifth intron of the PCSK9 gene and affects the splicing process of RNA, which may lead to reduced PCSK9 mRNA levels [ 39 ]. Rs2483205 is also located in the intronic region of the PCSK9 gene and regulates the promoter flanking regions.…”

Comparing the Relationships of Genetically Proxied PCSK9 Inhibition With Mood Disorders, Cognition, and Dementia Between Men and Women: A Drug‐Target Mendelian Randomization Study

“… 49 We clumped SNPs at linkage disequilibrium R 2 =0.001, leaving 6 independent SNPs comprising the LDL‐C–based PCSK9 instrument. Because only 3 of the 6 independent PCSK9 variants in the LDL‐C instrument were found in the PCSK9 protein level data, 50 we also created a PCSK9–LDL‐C instrument comprising only variants associated with both LDL‐C ( P <5×10 −8 ) and PCSK9 protein levels ( P <5×10 −6 ), 50 as a biologically conservative instrument and sensitivity analysis to assess the MR exclusion restriction assumption. We included an LDL‐C–based PCSK9 instrument with 3 independent SNPs derived from the earlier 2013 GLGC GWAS of circulating LDL‐C levels (N≤173 082) as an additional sensitivity analysis.…”

“…Next, because instrumentation of PCSK9 in LDL‐C does not measure changes in PCSK9 levels directly, and because current anti‐PCSK9 monoclonal antibodies target the PCSK9 protein, 44 we supplemented the PCSK9 instrument derived from LDL‐C data with SNPs associated with circulating PCSK9 protein levels using protein quantitative loci (pQTL) data from 10 186 individuals of European ancestry. 50 We extracted and clumped SNPs as above, leaving 2 independent SNPs within the PCSK9 locus. PCSK9 protein levels were measured in normalized protein units.…”

“…PCSK9 protein levels were measured in normalized protein units. 50 Given the liver‐specific mechanism of action of recently approved small interfering RNA inhibitor, inclisiran, 15 we extracted eQTL from GTEx version 8 52 PCSK9 data–derived liver tissue (N=178). We cis ‐instrumented the liver PCSK9 instrument (clumped at linkage disequilibrium R 2 =0.001), leaving one variant.…”