Novel rare and low frequency coding variants associated with LDL cholesterol levels. C. Willer1,2,3, L. A. Lange4, Y. Hu5, H. Zhang1, C. Xue2, E. M. Schmidt2, M. Boehnke5, L. Groop6,7, M. McCarthy8, T. Meitinger9, M. Fornage10,11, C. Ballantyne12, E. Boerwinkle11, D. Altshuler13,14,15,16, D.-y. Lin17, G. Jarvik18, L. A. Cupples19,20, C. Kooperberg21, J. G. Wilson22, D. A. Nickerson23, G. R. Abecasis5, S. S. Rich24, R. P. Tracy25,26, NHLBI Exome Sequencing Project 1) Department of Internal Medicine, Univ Michigan, Ann Arbor, MI; 2) Department of Computational Medicine and Bioinformtics, U of Michigan, Ann Arbor, MI; 3) Department of Human Genetics, University of Michigan, Ann Arbor, MI; 4) Department of Genetics, University of North Carolina, Chapel Hill, NC; 5) Department of Biostatistics, University of Michigan, Ann Arbor, MI; 6) Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, University Hospital Skåne, Malmö, Sweden; 7) Glostrup Research Institute, Glostrup University Hospital, Glostrup, Denmark; 8) Oxford Centre for Diabetes, Endocrinology and Metabolism and Oxford NIHR Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK; 9) Institute of Human Genetics, Hemholtz Center Munich, German Research Center for Environmental Health and Institute of Human Genetics, Technical University Munich, Neuherberg, Germany; 10) Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA; 11) Center for Human Genetics, University of Texas, Health Science Center at Houston, Houston, TX, USA; 12) Baylor College of Medicine, and Methodist DeBakey Heart and Vascular Center, Houston, TX, USA; 13) Program in Medical and Population Genetics, Broad Institute, Cambridge, MA; 14) Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA; 15) Department of Molecular Biology, Massachusetts General Hospital, Boston, MA; 16) Department of Genetics, Harvard Medical School, Boston, MA; 17) Department of Biostatistics, University of North Carolina, Chapel Hill, NC; 18) Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA, USA; 19) National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, MA; 20) Department of Biostatistics, Boston University School of Public Health, Boston, MA; 21) Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA; 22) Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS; 23) Department of Genome Sciences, University of Washington, Seattle, WA; 24) Center for Public Health Genomics, University of Virginia, Charlottesville, VA; 25) Department of Biochemistry, University of Vermont, Colchester, VT; 26) Department of Pathology, University of Vermont, Colchester, VT.

   Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies 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 1,302 additional individuals and genotype-based analysis of 52,222 individuals. We observed significant association between LDL-C and the burden of rare or low frequency variants for four genes: a new association at PNPLA5, a phospholipase domain containing gene, and novel as well as known variants in three known lipid genes: PCSK9, LDLR and APOB. We replicated the novel PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. The frequency, impact on protein structure, and effect sizes of associated rare variants differed among loci - from extremely rare loss-of-function variants in APOB to low frequency variants with more modest effect sizes in PCSK9. We present clear evidence that uncommon and rare variants contribute to variation of LDL-C levels in the general population. Our major specific findings are: 1) the identification of a novel LDL-C associated gene, PNPLA5; 2) the identification of known and novel variants in three previously identified genes LDLR, PCSK9, and APOB; and 3) the observation that associated variants have a range of minor allele frequency and putative functional importance which necessitates a variety of analytic approaches to optimize gene discovery.

You may contact the first author (during and after the meeting) at