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

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A phenome-wide association study to discover pleiotropic effects of PCSK9, APOB, and LDLR.
npj Genomic Medicine ( IF 4.7 ) Pub Date : 2019-02-11 , DOI: 10.1038/s41525-019-0078-7
Maya S Safarova ₁ , Benjamin A Satterfield ₁ , Xiao Fan ₁ , Erin E Austin ₁ , Zhan Ye ₂ , Lisa Bastarache ₃ , Neil Zheng ₃ , Marylyn D Ritchie ₄ , Kenneth M Borthwick ₅ , Marc S Williams ₆ , Eric B Larson ₇ , Aaron Scrol ₇ , Gail P Jarvik ₈ , David R Crosslin _{8,

9} , Kathleen Leppig ₁₀ , Laura J Rasmussen-Torvik ₁₁ , Sarah A Pendergrass ₅ , Amy C Sturm ₆ , Bahram Namjou ₁₂ , Amy Sanghavi Shah ₁₃ , Robert J Carroll ₃ , Wendy K Chung _{14,

15} , Wei-Qi Wei ₃ , QiPing Feng ₁₆ , C Michael Stein ₁₆ , Dan M Roden ₁₇ , Teri A Manolio ₁₈ , Daniel J Schaid ₁₉ , Joshua C Denny ₃ , Scott J Hebbring ₂₀ , Mariza de Andrade ₁₉ , Iftikhar J Kullo ₁

Affiliation

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

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.

中文翻译：

一项全表组关联研究，旨在发现 PCSK9、APOB 和 LDLR 的多效性作用。

我们进行了一项基于电子健康记录 (EHR) 的全表型关联研究 (PheWAS)，以发现三种脂蛋白代谢基因 PCSK9、APOB 和 LDLR 变异的多效性效应。使用高密度基因型数据，我们测试了这三个基因的变异与 51,700 名欧洲血统 (EA) 个体中的 1232 个 EHR 衍生的二元 phecodes 和 10,276 名非洲血统 (AA) 个体中的 585 个 phecodes 的关联；通过插补质量 (r 2 > 0.4)、次要等位基因频率 (>1%)、连锁不平衡 (r 2 < 0.3) 以及与 LDL-C 水平的关联对 457 个 PCSK9、730 个 APOB 和 720 个 LDLR 变异进行筛选，得出EA 中包含两个 PCSK9、三个 APOB 和五个 LDLR 变体，但 AA 中没有变体。使用 R 中的 PheWAS 包定义每个 phecode 的病例和对照。逻辑回归假设使用加性遗传模型并调整年龄、性别和前两个主成分。在范德比尔特大学 (n = 29,713)、Marshfield Clinic 个性化医学研究项目 (n = 9562) 和英国生物银行 (n = 408,455) 的其他队列中测试了显着相关性。我们鉴定出一种 PCSK9、两种 APOB 和两种 LDLR 变体与所检查的 phecode 显着相关。只有一种变异与非脂质疾病phecode（“近视”）相关，但这种关联在复制队列中并不显着。在这个大规模的 PheWAS 中，我们没有发现 PCSK9、APOB 和 LDLR 中的 LDL-C 相关变异与非脂质相关表型（包括糖尿病、神经认知障碍或白内障）相关。

更新日期：2019-02-11

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