Meta-GWAS of PCSK9 Levels Detects Two Novel Loci at APOB and TM6SF2

Overview

Journal Hum Mol Genet

Specialties Genetics
Molecular Biology

Date 2021 Sep 30

PMID 34590679

Citations 7

Authors

Janne Pott

Jesper R Gadin

Elizabeth Theusch

Marcus E Kleber

Graciela E Delgado

Holger Kirsten

Stefanie M Hauck

Ralph Burkhardt

Hubert Scharnagl

Ronald M Krauss

Markus Loeffler

Winfried Marz

Joachim Thiery

Angela Silveira

Ferdinand M Vant Hooft

Markus Scholz

Affiliations

Soon will be listed here.

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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