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Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol.
Lange, Leslie A; Hu, Youna; Zhang, He; Xue, Chenyi; Schmidt, Ellen M; Tang, Zheng-Zheng; Bizon, Chris; Lange, Ethan M; Smith, Joshua D; Turner, Emily H; Jun, Goo; Kang, Hyun Min; Peloso, Gina; Auer, Paul; Li, Kuo-Ping; Flannick, Jason; Zhang, Ji; Fuchsberger, Christian; Gaulton, Kyle; Lindgren, Cecilia; Locke, Adam; Manning, Alisa; Sim, Xueling; Rivas, Manuel A; Holmen, Oddgeir L; Gottesman, Omri; Lu, Yingchang; Ruderfer, Douglas; Stahl, Eli A; Duan, Qing; Li, Yun; Durda, Peter; Jiao, Shuo; Isaacs, Aaron; Hofman, Albert; Bis, Joshua C; Correa, Adolfo; Griswold, Michael E; Jakobsdottir, Johanna; Smith, Albert V; Schreiner, Pamela J; Feitosa, Mary F; Zhang, Qunyuan; Huffman, Jennifer E; Crosby, Jacy; Wassel, Christina L; Do, Ron; Franceschini, Nora; Martin, Lisa W; Robinson, Jennifer G.
Afiliación
  • Lange LA; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Hu Y; Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
  • Zhang H; Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
  • Xue C; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
  • Schmidt EM; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
  • Tang ZZ; Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Bizon C; Renaissance Computing Institute, Chapel Hill, NC 27517, USA.
  • Lange EM; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Smith JD; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
  • Turner EH; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
  • Jun G; Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
  • Kang HM; Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
  • Peloso G; Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA.
  • Auer P; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; School of Public Health, University of Wisconsin - Milwaukee, Milwaukee, WI 53201, USA.
  • Li KP; Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
  • Flannick J; Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Zhang J; Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
  • Fuchsberger C; Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
  • Gaulton K; Wellcome Trust Centre for Human Genetics, University of Oxford, OX1 2JD Oxford, UK.
  • Lindgren C; Wellcome Trust Centre for Human Genetics, University of Oxford, OX1 2JD Oxford, UK.
  • Locke A; Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
  • Manning A; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA; School of Public Health, University of Wisconsin - Milwaukee, Milwaukee, WI 53201, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA; Department of Genetics, Harvard Medical Scho
  • Sim X; Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
  • Rivas MA; Wellcome Trust Centre for Human Genetics, University of Oxford, OX1 2JD Oxford, UK.
  • Holmen OL; HUNT Research Center, Department of Public Health, Norwegian University of Science and Technology, 7600 Levanger, Norway.
  • Gottesman O; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Lu Y; The Genetics of Obesity and Related Metabolic Traits Program, The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Ruderfer D; Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Stahl EA; Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Duan Q; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Li Y; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, U
  • Durda P; Department of Pathology, University of Vermont, Colchester, VT 05446, USA.
  • Jiao S; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
  • Isaacs A; Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, 3015 DR Rotterdam, the Netherlands.
  • Hofman A; Department of Epidemiology, Erasmus University Medical Center, 3000 DR Rotterdam, the Netherlands.
  • Bis JC; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
  • Correa A; Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
  • Griswold ME; Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
  • Jakobsdottir J; Icelandic Heart Association, IS-201 Kopavogur, Iceland.
  • Smith AV; Icelandic Heart Association, IS-201 Kopavogur, Iceland; University of Iceland, 101 Reykjavik, Iceland.
  • Schreiner PJ; Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN 55454, USA.
  • Feitosa MF; Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • Zhang Q; Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • Huffman JE; Medical Research Center for Human Genetics, Medical Research Center Institute of Genetics and Molecular Medicine, University of Edinburgh, EH4 2XU Edinburgh, UK.
  • Crosby J; Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
  • Wassel CL; Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
  • Do R; Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA.
  • Franceschini N; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Martin LW; Division of Cardiology, George Washington School of Medicine and Health Sciences, Washington, DC 20037, USA.
  • Robinson JG; Departments of Epidemiology and Medicine, University of Iowa, Iowa City, IA 52242, USA.
Am J Hum Genet ; 94(2): 233-45, 2014 Feb 06.
Article en En | MEDLINE | ID: mdl-24507775
ABSTRACT
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 (>98(th) or <2(nd) 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.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Polimorfismo de Nucleótido Simple / Estudio de Asociación del Genoma Completo / Exoma / Frecuencia de los Genes / LDL-Colesterol Tipo de estudio: Etiology_studies / Incidence_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Adult / Aged / Female / Humans / Male / Middle aged Idioma: En Revista: Am J Hum Genet Año: 2014 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
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XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Polimorfismo de Nucleótido Simple / Estudio de Asociación del Genoma Completo / Exoma / Frecuencia de los Genes / LDL-Colesterol Tipo de estudio: Etiology_studies / Incidence_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Adult / Aged / Female / Humans / Male / Middle aged Idioma: En Revista: Am J Hum Genet Año: 2014 Tipo del documento: Article País de afiliación: Estados Unidos