A phenome-wide association study to discover pleiotropic effects of PCSK9, APOB, and LDLR

Maya Safarova ,Robert J Carroll,Daniel J Schaid,Kenneth M Borthwick,Amy C Sturm,David R Crosslin,Joshua C Denny,Erin Austin ,Sarah A Pendergrass,Laura J Rasmussen‐Torvik ,Aaron Scrol,Neil S Zheng ,C Michael Stein,Kathleen A Leppig ,Dan M Roden,Amy S Shah ,Marc S Williams,Teri A Manolio,Wei Qi Wei ,Marylyn D Ritchie,Eric B Larson,Wendy K Chung,Xiao Fan,Benjamin A Satterfield,Mariza De Andrade,Gail P Jarvik,Bahram Namjou,Zhan Ye,Lisa Bastarache,Scott J Hebbring,Feng Qi ,Iftikhar J Kullo

doi:10.1038/s41525-019-0078-7

Abstract

We conducted an electronic health record (EHR)-based phenome-wide association study (PheWAS) to discover pleiotropic effects of variants in three lipoprotein metabolism genes PCSK9, APOB, and LDLR. Using high-density genotype data, we tested the associations of variants in the three genes with 1232 EHR-derived binary phecodes in 51,700 European-ancestry (EA) individuals and 585 phecodes in 10,276 African-ancestry (AA) individuals; 457 PCSK9, 730 APOB, and 720 LDLR variants were filtered by imputation quality (r2 > 0.4), minor allele frequency (>1%), linkage disequilibrium (r2 < 0.3), and association with LDL-C levels, yielding a set of two PCSK9, three APOB, and five LDLR variants in EA but no variants in AA. Cases and controls were defined for each phecode using the PheWAS package in R. Logistic regression assuming an additive genetic model was used with adjustment for age, sex, and the first two principal components. Significant associations were tested in additional cohorts from Vanderbilt University (n = 29,713), the Marshfield Clinic Personalized Medicine Research Project (n = 9562), and UK Biobank (n = 408,455). We identified one PCSK9, two APOB, and two LDLR variants significantly associated with an examined phecode. Only one of the variants was associated with a non-lipid disease phecode, (“myopia”) but this association was not significant in the replication cohorts. In this large-scale PheWAS we did not find LDL-C-related variants in PCSK9, APOB, and LDLR to be associated with non-lipid-related phenotypes including diabetes, neurocognitive disorders, or cataracts.

Highlights

Genetic pleiotropy is widespread; ~5% of common variants and~17% of genomic regions are associated with more than one phenotype.[1]
After applying quality control filters and other selection criteria including association with low-density lipoprotein-cholesterol (LDL-C), for the primary analysis, two proprotein convertase subtilisin/kexin type 9 (PCSK9), three apolipoprotein B (APOB), and five lowdensity lipoprotein receptor (LDLR) variants remained for phenome-wide association study (PheWAS) analysis in the EA cohort, but no variants remained for PheWAS analysis for the AA cohort (Fig. 1 and Table 2)
To determine whether variants not associated with LDL-C levels in the three genes were associated with other phenotypes, a secondary analysis was performed with a similar selection process in the discovery cohort that included “missense” variants not associated with LDL-C

Summary

Introduction

~17% of genomic regions are associated with more than one phenotype.[1] Genes implicated in lipoprotein metabolism are no exception and have been reported to be associated with type 2 diabetes.[2,3,4,5] The National Human Genome Research Institute-. European Bioinformatics Institute (NHGRI-EBI) Genome-wide Association Study (GWAS) catalog[4] lists additional possible associations of variants near these genes with diverse diseases including Wilms’ tumor, allergic rhinitis, and bipolar disorder among others. Drugs targeting genes or gene products involved in lipoprotein metabolism may have unintended effects.[6,7] Pathogenic variants in proprotein convertase subtilisin/kexin type 9 (PCSK9), apolipoprotein B (APOB), and lowdensity lipoprotein receptor (LDLR) can lead to familial hypercholesterolemia (FH). The gene product of APOB is found on LDL particles and is the ligand for LDLR.[9]

Methods

Results

Conclusion