A large electronic health record-based genome-wide study of serum lipids

A genome-wide association study of 94,674 multi-ethnic Kaiser Permanente members utilizing 478,866 longitudinal untreated serum lipid electronic-health-record-derived measurements (EHRs) empowered multiple novel findings: 121 new SNP associations (46 primary, 15 conditional, 60 in meta-analysis with Global Lipids Genetic Consortium); increase of 33-42% in variance explained with multiple measurements; sex differences in genetic impact (greater in females for LDL, HDL, TC, the opposite for TG); differences in variance explained amongst non-Hispanic whites, Latinos, African Americans, and East Asians; genetic dominance and epistasis, with strong evidence for both at ABOxFUT2 for LDL; and eQTL tissue-enrichment implicating the liver, adipose, and pancreas. Utilizing EHR pharmacy data, both LDL and TG 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 novel genetic features of cholesterol and lipoprotein metabolism with implications for lipid treatment and risk of coronary heart disease.