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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We are grateful to the Kaiser Permanente Northern California members who have generously agreed to participate in the Kaiser Permanente Research Program on Genes, Environment, and Health. We would like to thank R. Dobrin for his contribution of the liver and adipose eQTL results table from the RYGB cohort. This work was supported by NIH P50 GM115318 to R.M.K., which partially supported T.H., E.T., M.W.M., C.I., C.S., E.J., R.M.K., and N.R. This work was supported by grants R21 AG046616 and K01 DC013300 to T.J.H. from the US National Institutes of Health for imputation. Support for participant enrollment, survey completion, and biospecimen collection for the RPGEH was provided by the Robert Wood Johnson Foundation, the Wayne and Gladys Valley Foundation, the Ellison Medical Foundation, and Kaiser Permanente national and regional community benefit programs. Genotyping of the GERA cohort was funded by a grant from the National Institute on Aging, the National Institute of Mental Health, and the National Institutes of Health Common Fund (RC2 AG036607 to C.S. and N.R.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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  1. Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA

    • Thomas J. Hoffmann
    • , Tanushree Haldar
    • , Mark N. Kvale
    • , Pui-Yan Kwok
    •  & Neil Risch
  2. Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA

    • Thomas J. Hoffmann
    •  & Neil Risch
  3. Children’s Hospital Oakland Research Institute, Oakland, CA, USA

    • Elizabeth Theusch
    • , Marisa W. Medina
    •  & Ronald M. Krauss
  4. Division of Research, Kaiser Permanente, Northern California, Oakland, CA, USA

    • Dilrini K. Ranatunga
    • , Eric Jorgenson
    • , Catherine Schaefer
    • , Carlos Iribarren
    •  & Neil Risch


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T.J.H., E.T., T.H., E.J., M.W.M., C.S., R.M.K., C.I., and N.R. conceived and designed the study. P.-Y.K. supervised the creation of genotype data. D.K.R., in collaboration with C.I., C.S., N.R., and T.J.H., extracted phenotype data from the EHRs. T.J.H., E.T., T.H., D.K.R., and N.R. performed the statistical analysis. T.J.H., E.T., T.H., D.K.R., E.J., M.W.M., C.S., R.M.K., C.I., and N.R. interpreted the results of analysis. T.J.H., E.T., T.H., D.K.R., E.J., M.W.M., M.N.K., P.-Y.K., C.S., R.M.K., C.I., and N.R. contributed to the drafting and critical review of the manuscript.

Competing interests

The authors declare no competing interests.

Corresponding authors

Correspondence to Thomas J. Hoffmann or Neil Risch.

Supplementary information

  1. Supplementary Text and Figures

    Supplementary Figures 1 and 3–14, and Supplementary Tables 1, 2, 10, 11, and 13–17

  2. Life Sciences Reporting Summary

  3. Supplementary Figure 2

    Plots of each genetic locus

  4. Supplementary Table 3

    Novel GERA lipid results

  5. Supplementary Table 4

    GERA results for previously identified loci

  6. Supplementary Table 6

    Novel GERA + GLGC lipid results

  7. Supplementary Table 8

    Conditional SNP results

  8. Supplementary Table 12

    Discovery was done in the fixed-effects meta-analysis (n = 94,674) of GERA non-Hispanic whites (n = 76,627), Latinos (n = 7,795), East Asians (n = 6,855), African Americans (n = 2,958), and South Asians (n = 439), each using linear regression

  9. Supplementary Tables 5, 7 and 9

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