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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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 -
