Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol

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181 Scopus citations


Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98th or <2nd percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.

Original languageEnglish
Pages (from-to)233-245
Number of pages13
JournalAmerican Journal of Human Genetics
Issue number2
StatePublished - Feb 6 2014

Bibliographical note

Funding Information:
The authors wish to acknowledge the support of the NHLBI and the contributions of the research institutions, study investigators, field staff, and study participants in creating this resource for biomedical research. Funding for the NHLBI Grand Opportunity (GO) Exome Sequencing Project was provided by NHLBI grants RC2 HL-103010 (HeartGO), RC2 HL-102923 (LungGO), and RC2 HL-102924 (Women’s Health Initiative Sequencing Project). Exome sequencing was performed through NHLBI grants RC2 HL-102925 (BroadGO) and RC2 HL-102926 (SeattleGO). G.J. is supported by R01 HL67406 and the Northwest Institute of Genomic Medicine, funded by the Washington State Life Sciences Discovery Fund. S.K.’s effort is funded through National Institutes of Health grant R01HL107816. C.J.W. is supported by R00 HL94535 and R01 HL109946. The University of Iowa receives financial support from Amarin, Amgen, Astra-Zeneca, Daiichi-Sankyo, Esperion, F. Hoffman-La Roche, Glaxo-Smith Kline, Merck, Regeneron and Sanofi, and Takeda and Zinfandel for J.G.R’s research. B.M.P serves on the data and safety monitoring board of a clinical trial for Zoll LifeCor. Additional acknowledgements are provided in the Supplemental Data.

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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