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Meta-Analysis
. 2022 Mar 21;31(6):999-1011.
doi: 10.1093/hmg/ddab279.

Meta-GWAS of PCSK9 levels detects two novel loci at APOB and TM6SF2

Janne Pott  1   2 , Jesper R Gådin  3 , Elizabeth Theusch  4 , Marcus E Kleber  5   6 , Graciela E Delgado  5 , Holger Kirsten  1   2 , Stefanie M Hauck  7 , Ralph Burkhardt  2   8   9 , Hubert Scharnagl  10 , Ronald M Krauss  4   11 , Markus Loeffler  1   2 , Winfried März  5   10   12 , Joachim Thiery  2   8   13 , Angela Silveira  3 , Ferdinand M Van't Hooft  3 , Markus Scholz  1   2
Affiliations
Meta-Analysis

Meta-GWAS of PCSK9 levels detects two novel loci at APOB and TM6SF2

Janne Pott et al. Hum Mol Genet. .

Abstract

Background: 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).

Methods and 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. Although the causal effect of PCSK9 on CAD is mainly mediated by LDL-C, an independent direct effect also occurs.

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Figures

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Graphical abstract
Figure 1
Figure 1
Miami plot. Distribution of log10-transformed P-values of our GWAMA for all (top, −log10) and the statin free subset (bottom, + log10). The red dashed and blue dotted lines mark genome-wide significance (α = 5 × 10–8) and suggestive significance (α = 1 × 10–6), respectively. The Y-axis is limited to [−20, 20] (max. and min. Original y-value: 48.0 for all, −45.8 for sub). Four distinct loci with genome-wide significance were found and their candidate genes are given in black for the best associating group. Candidate genes of suggestive loci are shown in grey. QQ-plots are given in the Supplementary Material, Fig. S1.
Figure 2
Figure 2
Regional association (RA) plots of the locus 1p32.3. The respective lead SNP is colored blue, the other SNPs are colored according to their LD with the lead SNP (using 1000 Genomes Phase 3, Europeans only). (A)–(C) RA plots of the independent variants with statistics conditioned on the respective other independent variants. (D) RA plot of the unconditional statistics with rs11591147 as lead SNP. Red circles indicate the two other independent signals, rs2495477 and rs11306510.
Figure 3
Figure 3
Results of pairwise co-localization for the genome-wide significant loci and other lipid traits, CAD and eQTLs. Maximum of PP4 and PP3 are shown. Blue indicates a high posterior probability of co-localization (PP4, both traits share the same causal variant), and red a high posterior probability for two independent associations at this locus (PP3). White cells indicate that there is no signal for the trait compared. For the eQTL comparison, only the maximum PP4 value over independent SNPs and eQTL tissues was displayed per locus.
See this image and copyright information in PMC

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