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Whole-genome sequence–based analysis of high-density lipoprotein cholesterol

Nature Genetics volume 45, pages 899–901 (2013)Cite this article

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Abstract

We describe initial steps for interrogating whole-genome sequence data to characterize the genetic architecture of a complex trait, levels of high-density lipoprotein cholesterol (HDL-C). We report whole-genome sequencing and analysis of 962 individuals from the Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) studies. From this analysis, we estimate that common variation contributes more to heritability of HDL-C levels than rare variation, and screening for mendelian variants for dyslipidemia identified individuals with extreme HDL-C levels. Whole-genome sequencing analyses highlight the value of regulatory and non-protein-coding regions of the genome in addition to protein-coding regions.

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Figure 1: Distribution of HDL-C levels for carriers of identified mendelian variation.
Figure 2: Survey of the genomic landscape using Lachesis.

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Acknowledgements

Atherosclerosis Risk in Communities (ARIC) Study: This ARIC study is carried out as a collaborative study supported by NHLBI contracts HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C and HHSN268201100012C. The authors thank the staff and participants of the ARIC study for their important contributions. Ancillary study support has been provided by NHLBI-sponsored project RC2HL102419-02.

Cardiovascular Health Study (CHS): This CHS research was supported by NHLBI contracts N01-HC-85239, N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133 and HHSN268201200036C and by NHLBI grants HL080295, HL087652 and HL105756, with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through AG-023629, AG-15928, AG-20098 and AG-027058 from the National Institute on Aging (NIA). See also https://chs-nhlbi.org/CHSOverview.

Framingham Heart Study (FHS) of the NHLBI of the US National Institutes of Health and Boston University School of Medicine: This work was supported by the NHLBI FHS (contract N01-HC-25195).

Author information

Author notes

  1. Alanna C Morrison, Arend Voorman, Andrew D Johnson and Xiaoming Liu: These authors contributed equally to this work.

Authors and Affiliations

  1. Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas, USA

    Alanna C Morrison, Xiaoming Liu, Alexander Li & Eric Boerwinkle

  2. Department of Biostatistics, University of Washington, Seattle, Washington, USA

    Arend Voorman & Kenneth Rice

  3. National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study, Framingham, Massachusetts, USA

    Andrew D Johnson, Christopher J O'Donnell & L Adrienne Cupples

  4. Division of Intramural Research, NHLBI, US National Institutes of Health, Bethesda, Maryland, USA,

    Andrew D Johnson & Christopher J O'Donnell

  5. Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA

    Jin Yu, Donna Muzny, Fuli Yu, Richard Gibbs & Eric Boerwinkle

  6. Department of Agronomy, Kansas State University, Manhattan, Kansas, USA

    Chengsong Zhu

  7. Departments of Medicine, Cardiovascular Health Research Unit, Epidemiology and Health Services, University of Washington, Seattle, Washington, USA

    Joshua Bis & Bruce M Psaty

  8. Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA

    Gerardo Heiss

  9. Group Health Research Institute, Group Health Cooperative, Seattle, Washington, USA

    Bruce M Psaty

  10. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA

    L Adrienne Cupples

Consortia

the Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) Consortium

  • Alanna C Morrison
  • , Arend Voorman
  • , Andrew D Johnson
  • , Xiaoming Liu
  • , Jin Yu
  • , Alexander Li
  • , Donna Muzny
  • , Fuli Yu
  • , Kenneth Rice
  • , Chengsong Zhu
  • , Joshua Bis
  • , Gerardo Heiss
  • , Christopher J O'Donnell
  • , Bruce M Psaty
  • , L Adrienne Cupples
  • , Richard Gibbs
  •  & Eric Boerwinkle

Contributions

J.Y., D.M., F.Y., E.B. and R.G. were responsible for the design and implementation of the whole-genome sequencing and variant calling. A.L. and K.R. contributed to the analysis of mendelian variation. X.L. and C.Z. contributed to the estimation of heritability. A.C.M., A.V. and A.D.J. performed statistical analysis of the whole-genome sequence and phenotype data. G.H., C.J.O. and B.M.P. were involved in participant recruitment, consenting and examination. A.C.M., A.V., A.D.J., X.L., J.B., G.H., C.J.O., B.M.P., L.A.C., R.G. and E.B. jointly conceived the study and contributed to preparation and editing of the manuscript.

Corresponding author

Correspondence to Eric Boerwinkle.

Ethics declarations

Competing interests

B.M.P. serves on the Data and Safety Monitoring Board for a clinical trial of a device funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Medtronic.

Supplementary information

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Supplementary Figures 1–11, Supplementary Tables 1–7, Supplementary Note (PDF 412 kb)

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the Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) Consortium. Whole-genome sequence–based analysis of high-density lipoprotein cholesterol. Nat Genet 45, 899–901 (2013). https://doi.org/10.1038/ng.2671

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