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


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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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

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).

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Authors and Affiliations



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.

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Correspondence to Eric Boerwinkle.

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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.

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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).

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