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A large electronic-health-record-based genomewide study of serum lipids

by Krauss, Ronald M , Jorgenson, Eric , Medina, Marisa W , Kwok, Pui-Yan , Theusch, Elizabeth , Schaefer, Catherine , Risch, Neil , Iribarren, Carlos , Hoffmann, Thomas J , Kvale, Mark N , Ranatunga, Dilrini K , Haldar, Tanushree

in African Americans / Age / Body mass index / Cardiovascular disease / Cardiovascular diseases / Cholesterol / Consortia / Coronary artery disease / Electronic health records / Electronic medical records / Epistasis / Gender aspects / Gene expression / Genetic analysis / Genome-wide association studies / Genomes / Genotype & phenotype / Heart diseases / High density lipoprotein / Hispanic Americans / Lipid metabolism / Lipids / Liver / Low density lipoprotein / Meta-analysis / Metabolism / Pancreas / Serum lipids / Sex differences / Single-nucleotide polymorphism / Triglycerides

2018

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A large electronic-health-record-based genomewide study of serum lipids

2018

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2018

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Journal Article

A large electronic-health-record-based genomewide study of serum lipids

Krauss, Ronald M,

Jorgenson, Eric,

Medina, Marisa W,

Kwok, Pui-Yan,

Theusch, Elizabeth,

Schaefer, Catherine,

Risch, Neil,

Iribarren, Carlos,

Hoffmann, Thomas J,

Kvale, Mark N,

Ranatunga, Dilrini K,

Haldar, Tanushree

2018

Overview

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.

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Publisher

Nature Publishing Group

Subject

African Americans

/ Age

/ Body mass index

/ Cardiovascular disease

/ Cardiovascular diseases

/ Cholesterol

/ Consortia