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NPJ Genom Med. 2019 Feb 11;4:3. doi: 10.1038/s41525-019-0078-7. eCollection 2019.

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

Author information

1
1Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55905 USA.
2
2Biomedical Informatics Research Center, Marshfield Clinic Research Foundation, Marshfield, WI 54449 USA.
3
3Department of Biomedical Informatics, Vanderbilt University, Nashville, TN 37235 USA.
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4Department of Genetics, University of Pennsylvania, Philadelphia, PA 19111 USA.
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Department of Biomedical and Translational Informatics, Geisinger, Danville, PA 17821 USA.
6
Genomic Medicine Institute, Geisinger, Danville, PA 17822 USA.
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7Group Health Research Institute, Seattle, WA 98101 USA.
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8Department of Medicine (Medical Genetics), University of Washington Medical Center, Seattle, WA 98195 USA.
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9Department of Genome Sciences, University of Washington, Seattle, WA 98195 USA.
10
Genetic Services, Kaiser Permanente of Washington, Seattle, WA 98122 USA.
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11Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 USA.
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12Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, and Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, OH 45229 USA.
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13Division of Endocrinology, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, OH 45229 USA.
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14Department of Pediatrics, Columbia University, New York, NY 10032 USA.
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15Department of Medicine, Columbia University, New York, NY 10032 USA.
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16Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University, Nashville, TN 37232 USA.
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17Department of Medicine, Vanderbilt University, Nashville, TN 37232 USA.
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18Division of Genomic Medicine, National Human Genome Research Institute, Bethesda, MD 20892 USA.
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19Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905 USA.
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20Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WI 54449 USA.
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Contributed equally

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 (r 2 > 0.4), minor allele frequency (>1%), linkage disequilibrium (r 2 < 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.

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