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 Shah; Robert 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 J. Kullo

doi:10.1038/s41525-019-0078-7

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 J. Kullo^*

^*Corresponding author for this work

Preventive Medicine

Research output: Contribution to journal › Article › peer-review

23 Scopus citations

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 language	English (US)
Article number	3
Journal	npj Genomic Medicine
Volume	4
Issue number	1
DOIs	https://doi.org/10.1038/s41525-019-0078-7
State	Published - Dec 1 2019

Funding

We are indebted to the investigators and participants of DNA biorepositories across the electronic Medical Records and Genomics Network. This work was supported by the National Human Genome Research Institute’s electronic Medical Records and Genomics Network through grants U01HG04599 and U01HG006379 (Mayo Clinic, Rochester, Minnesota), U01HG006378 (Vanderbilt University Medical Center, Nashville, Tennessee), U01HG04603 and U01HG006385 (Vanderbilt University Medical Center serving as the Coordinating Center), U01HG004608 (Marshfield Clinic, Marshfield, Wisconsin), U01HG006389 (Marshfield Clinic Research Foundation and Pennsylvania State University), U01HG006382 (Geisinger Clinic, Danville, Pennsylvania), U01HG004610 and U01HG006375 (University of Washington/Group Health Research Institute, Seattle, Washington), U01HG004609 and U01HG006388 (North-western University, Chicago, Illinois), U01HG006380 (Icahn School of Medicine at Mount Sinai, New York, New York), U01HG008680 (Columbia University, New York, New York), U01HG004438 (CIDR) and U01HG004424 (the Broad Institute) serving as Genotyping Centers. I.J.K. was additionally supported by American Heart Association grant 17IG33660937 and by NIH grant K24HL137010. M.S.S. was funded by American Heart Association Postdoctoral Fellowship Award 16POST27280004. Q.F. was supported by NIH grant R01GM120523. W.Q. was supported by NIH grant R01HL133786. The American Heart Association (Dallas, TX) had no role in the design and conduct of the work; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

ASJC Scopus subject areas

Genetics(clinical)
Genetics
Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41525-019-0078-7

Cite this

Safarova, M. S., Satterfield, B. A., Fan, X., Austin, E. E., Ye, Z., Bastarache, L., Zheng, N., Ritchie, M. D., Borthwick, K. M., Williams, M. S., Larson, E. B., Scrol, A., Jarvik, G. P., Crosslin, D. R., Leppig, K., Rasmussen-Torvik, L. J., Pendergrass, S. A., Sturm, A. C., Namjou, B., ... Kullo, I. J. (2019). A phenome-wide association study to discover pleiotropic effects of PCSK9, APOB, and LDLR. npj Genomic Medicine, 4(1), Article 3. https://doi.org/10.1038/s41525-019-0078-7

@article{3c3431e7130747ae8adc93dbdc8c5aab,

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

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.",

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

note = "Funding Information: We are indebted to the investigators and participants of DNA biorepositories across the electronic Medical Records and Genomics Network. This work was supported by the National Human Genome Research Institute{\textquoteright}s electronic Medical Records and Genomics Network through grants U01HG04599 and U01HG006379 (Mayo Clinic, Rochester, Minnesota), U01HG006378 (Vanderbilt University Medical Center, Nashville, Tennessee), U01HG04603 and U01HG006385 (Vanderbilt University Medical Center serving as the Coordinating Center), U01HG004608 (Marshfield Clinic, Marshfield, Wisconsin), U01HG006389 (Marshfield Clinic Research Foundation and Pennsylvania State University), U01HG006382 (Geisinger Clinic, Danville, Pennsylvania), U01HG004610 and U01HG006375 (University of Washington/Group Health Research Institute, Seattle, Washington), U01HG004609 and U01HG006388 (North-western University, Chicago, Illinois), U01HG006380 (Icahn School of Medicine at Mount Sinai, New York, New York), U01HG008680 (Columbia University, New York, New York), U01HG004438 (CIDR) and U01HG004424 (the Broad Institute) serving as Genotyping Centers. I.J.K. was additionally supported by American Heart Association grant 17IG33660937 and by NIH grant K24HL137010. M.S.S. was funded by American Heart Association Postdoctoral Fellowship Award 16POST27280004. Q.F. was supported by NIH grant R01GM120523. W.Q. was supported by NIH grant R01HL133786. The American Heart Association (Dallas, TX) had no role in the design and conduct of the work; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41525-019-0078-7",

language = "English (US)",

volume = "4",

journal = "npj Genomic Medicine",

issn = "2056-7944",

publisher = "Nature Publishing Group",

number = "1",

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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

TY - JOUR

T1 - A phenome-wide association study to discover pleiotropic effects of PCSK9, APOB, and LDLR

AU - Safarova, Maya S.

AU - Satterfield, Benjamin A.

AU - Fan, Xiao

AU - Austin, Erin E.

AU - Ye, Zhan

AU - Bastarache, Lisa

AU - Zheng, Neil

AU - Ritchie, Marylyn D.

AU - Borthwick, Kenneth M.

AU - Williams, Marc S.

AU - Larson, Eric B.

AU - Scrol, Aaron

AU - Jarvik, Gail P.

AU - Crosslin, David R.

AU - Leppig, Kathleen

AU - Rasmussen-Torvik, Laura J.

AU - Pendergrass, Sarah A.

AU - Sturm, Amy C.

AU - Namjou, Bahram

AU - Shah, Amy Sanghavi

AU - Carroll, Robert J.

AU - Chung, Wendy K.

AU - Wei, Wei Qi

AU - Feng, Qi Ping

AU - Stein, C. Michael

AU - Roden, Dan M.

AU - Manolio, Teri A.

AU - Schaid, Daniel J.

AU - Denny, Joshua C.

AU - Hebbring, Scott J.

AU - de Andrade, Mariza

AU - Kullo, Iftikhar J.

N1 - Funding Information: We are indebted to the investigators and participants of DNA biorepositories across the electronic Medical Records and Genomics Network. This work was supported by the National Human Genome Research Institute’s electronic Medical Records and Genomics Network through grants U01HG04599 and U01HG006379 (Mayo Clinic, Rochester, Minnesota), U01HG006378 (Vanderbilt University Medical Center, Nashville, Tennessee), U01HG04603 and U01HG006385 (Vanderbilt University Medical Center serving as the Coordinating Center), U01HG004608 (Marshfield Clinic, Marshfield, Wisconsin), U01HG006389 (Marshfield Clinic Research Foundation and Pennsylvania State University), U01HG006382 (Geisinger Clinic, Danville, Pennsylvania), U01HG004610 and U01HG006375 (University of Washington/Group Health Research Institute, Seattle, Washington), U01HG004609 and U01HG006388 (North-western University, Chicago, Illinois), U01HG006380 (Icahn School of Medicine at Mount Sinai, New York, New York), U01HG008680 (Columbia University, New York, New York), U01HG004438 (CIDR) and U01HG004424 (the Broad Institute) serving as Genotyping Centers. I.J.K. was additionally supported by American Heart Association grant 17IG33660937 and by NIH grant K24HL137010. M.S.S. was funded by American Heart Association Postdoctoral Fellowship Award 16POST27280004. Q.F. was supported by NIH grant R01GM120523. W.Q. was supported by NIH grant R01HL133786. The American Heart Association (Dallas, TX) had no role in the design and conduct of the work; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Publisher Copyright: © 2019, The Author(s).

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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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UR - http://www.scopus.com/inward/citedby.url?scp=85061355814&partnerID=8YFLogxK

U2 - 10.1038/s41525-019-0078-7

DO - 10.1038/s41525-019-0078-7

M3 - Article

C2 - 30774981

AN - SCOPUS:85061355814

SN - 2056-7944

VL - 4

JO - npj Genomic Medicine

JF - npj Genomic Medicine

IS - 1

M1 - 3

ER -

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

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