基于大型电子健康记录的血脂全基因组研究。
A large electronic-health-record-based genome-wide study of serum lipids.
机构信息
Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
出版信息
Nat Genet. 2018 Mar;50(3):401-413. doi: 10.1038/s41588-018-0064-5. Epub 2018 Mar 5.
A genome-wide association study (GWAS) of 94,674 ancestrally diverse Kaiser Permanente members using 478,866 longitudinal electronic health record (EHR)-derived measurements for untreated serum lipid levels empowered multiple new findings: 121 new SNP associations (46 primary, 15 conditional, and 60 in meta-analysis with Global Lipids Genetic Consortium data); an increase of 33-42% in variance explained with multiple measurements; sex differences in genetic impact (greater impact in females for LDL, HDL, and total cholesterol and the opposite for triglycerides); differences in variance explained among non-Hispanic whites, Latinos, African Americans, and East Asians; genetic dominance and epistatic interaction, with strong evidence for both at the ABO and FUT2 genes for LDL; and tissue-specific enrichment of GWAS-associated SNPs among liver, adipose, and pancreas eQTLs. Using EHR pharmacy data, both LDL and triglyceride genetic risk scores (477 SNPs) were strongly predictive of age at initiation of lipid-lowering treatment. These findings highlight the value of longitudinal EHRs for identifying new genetic features of cholesterol and lipoprotein metabolism with implications for lipid treatment and risk of coronary heart disease.
一项针对 94674 名具有不同祖先背景的 Kaiser Permanente 成员的全基因组关联研究（GWAS），使用了 478866 份未经治疗的血清脂质水平的纵向电子健康记录（EHR）衍生测量值，产生了多个新发现：121 个新的 SNP 关联（46 个原发性、15 个条件性和 60 个与全球脂质遗传联盟数据的荟萃分析）；通过多次测量，解释方差的能力提高了 33-42%；遗传影响的性别差异（LDL、HDL 和总胆固醇在女性中影响更大，而甘油三酯则相反）；非西班牙裔白人、拉丁裔、非裔美国人和东亚人之间解释方差的差异；遗传显性和上位性相互作用，在 LDL 的 ABO 和 FUT2 基因中均有强烈证据；GWAS 相关 SNP 在肝脏、脂肪和胰腺 eQTL 中的组织特异性富集。使用 EHR 药房数据，LDL 和甘油三酯的遗传风险评分（477 个 SNP）强烈预测了降脂治疗开始的年龄。这些发现突出了纵向 EHR 在识别胆固醇和脂蛋白代谢新的遗传特征方面的价值，对脂质治疗和冠心病风险具有重要意义。
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