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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number3
Journalnpj Genomic Medicine
Volume4
Issue number1
DOIs
StatePublished - Dec 1 2019

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Electronic Health Records
Precision Medicine
Genetic Models
Myopia
Linkage Disequilibrium
Gene Frequency
Cataract
Genes
Lipoproteins
Logistic Models
Genotype
Phenotype
Research
oxidized low density lipoprotein
Neurocognitive Disorders

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

A phenome-wide association study to discover pleiotropic effects of PCSK9, APOB, and LDLR. / Safarova, Maya S.; Satterfield, Benjamin A.; Fan, Xiao; Austin, Erin E.; Ye, Zhan; Bastarache, Lisa; Zheng, Neil; Ritchie, Marylyn D.; Borthwick, Kenneth M.; Williams, Marc S.; Larson, Eric B.; Scrol, Aaron; Jarvik, Gail P.; Crosslin, David R.; Leppig, Kathleen; Rasmussen-Torvik, Laura J.; Pendergrass, Sarah A.; Sturm, Amy C.; Namjou, Bahram; Shah, Amy Sanghavi; Carroll, Robert J.; Chung, Wendy K.; Wei, Wei Qi; Feng, Qi Ping; Stein, C. Michael; Roden, Dan M.; Manolio, Teri A.; Schaid, Daniel J; Denny, Joshua C.; Hebbring, Scott J.; De Andrade, Mariza; Kullo, Iftikhar Jan.

In: npj Genomic Medicine, Vol. 4, No. 1, 3, 01.12.2019.

Research output: Contribution to journalArticle

Safarova, MS, Satterfield, BA, Fan, X, Austin, EE, Ye, Z, Bastarache, L, Zheng, N, Ritchie, MD, Borthwick, KM, Williams, MS, Larson, EB, Scrol, A, Jarvik, GP, Crosslin, DR, Leppig, K, Rasmussen-Torvik, LJ, Pendergrass, SA, Sturm, AC, Namjou, B, Shah, AS, Carroll, RJ, Chung, WK, Wei, WQ, Feng, QP, Stein, CM, Roden, DM, Manolio, TA, Schaid, DJ, Denny, JC, Hebbring, SJ, De Andrade, M & Kullo, IJ 2019, 'A phenome-wide association study to discover pleiotropic effects of PCSK9, APOB, and LDLR', npj Genomic Medicine, vol. 4, no. 1, 3. https://doi.org/10.1038/s41525-019-0078-7
Safarova, Maya S. ; Satterfield, Benjamin A. ; Fan, Xiao ; Austin, Erin E. ; Ye, Zhan ; Bastarache, Lisa ; Zheng, Neil ; Ritchie, Marylyn D. ; Borthwick, Kenneth M. ; Williams, Marc S. ; Larson, Eric B. ; Scrol, Aaron ; Jarvik, Gail P. ; Crosslin, David R. ; Leppig, Kathleen ; Rasmussen-Torvik, Laura J. ; Pendergrass, Sarah A. ; Sturm, Amy C. ; Namjou, Bahram ; Shah, Amy Sanghavi ; Carroll, Robert J. ; Chung, Wendy K. ; Wei, Wei Qi ; Feng, Qi Ping ; Stein, C. Michael ; Roden, Dan M. ; Manolio, Teri A. ; Schaid, Daniel J ; Denny, Joshua C. ; Hebbring, Scott J. ; De Andrade, Mariza ; Kullo, Iftikhar Jan. / A phenome-wide association study to discover pleiotropic effects of PCSK9, APOB, and LDLR. In: npj Genomic Medicine. 2019 ; Vol. 4, No. 1.
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AU - Namjou, Bahram

AU - Shah, Amy Sanghavi

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AU - Stein, C. Michael

AU - Roden, Dan M.

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