Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks

Lindsay M Reynolds; Riccardo E Marioni; Abbas Dehghan; Oscar H Franco; Aniruddh P Patel; Yingchang Lu; George Hindy; Omri Gottesman; Erwin P Bottinger; Olle Melander; Marju Orho-Melander; Ruth J F Loos; Stefano Duga; Piera Angelica Merlini; Martin Farrall; Anuj Goel; Rosanna Asselta; Domenico Girelli; Nicola Martinelli; Svati H Shah; Gina M Peloso; William E Kraus; Daniel J Rader; Alexander P Reiner; Paul L Auer; Muredach P Reilly; Caroline Hayward; Ruth McPherson; Hugh Watkins; Joshua C Bis; Ozren Polasek; Diego Ardissino; Arend Voorman; Qunyuan Zhang; Judy Wang; Ian J Deary; Michael Y Tsai; Alanna C Morrison; Herman A Taylor; Ingrid B Borecki; Adolfo Correa; Nathan O Stitziel; Michael E Griswold; Vilmundur Gudnason; Leslie A Lange; Jennifer A Brody; John M Starr; James G Wilson; Sumeet A Khetarpal; Igor Rudan; Gudny Eiriksdottir; Cornelia M van Duijn; Lenore J Launer; Jacy R Crosby; Jose M Ordovas; Charles Kooperberg; Myriam Fornage; Daniel Levy; Y-D Ida Chen; Stephen S Rich; Megan L Grove; Aaron Isaacs; Paolo Zanoni; Bruce M Psaty; Valeska Redon; Johanna Jakobsdottir; Jerome I Rotter; Serkalem Demissie; Kim Lawson; Mary F Feitosa; Ulrike Peters; Christopher J O'Donnell; Gail Davies; Christopher Carlson; Rebecca D Jackson; Kenneth Rice; Jennifer E Huffman; Kelli K Ryckman; Rachel H Mackey; Eric Boerwinkle; Jennifer G Robinson; Ani Manichaikul; David S Siscovick; Sekar Kathiresan; Brian Davis; Pamela J Schreiner; Josyf C Mychaleckyj; L Adrienne Cupples; Kurt Lohman; James S Pankow; Albert Hofman; Mingyao Li; Aron Y Joon; Andre G Uitterlinden; Tamara B Harris; Yongmei Liu; Kent D Taylor; Albert V Smith; Jeanette M Stafford; NHLBI GO Exome Sequencing Project

doi:10.1016/j.ajhg.2014.01.009

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Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks

Journal article

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Peer reviewed

Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks

Lindsay M Reynolds, Riccardo E Marioni, Abbas Dehghan, Oscar H Franco, Aniruddh P Patel, Yingchang Lu, George Hindy, Omri Gottesman, Erwin P Bottinger, Olle Melander, …

American journal of human genetics, Vol.94(2), pp.223-232

02/06/2014

DOI: 10.1016/j.ajhg.2014.01.009

PMCID: PMC3928662

PMID: 24507774

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Abstract

Low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121*], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited.

Phenotype

Genetic Code

Microtubule-Associated Proteins - genetics

Microtubule-Associated Proteins - metabolism

Humans

Middle Aged

Male

Genetic Variation

1-Alkyl-2-acetylglycerophosphocholine Esterase - genetics

Adult

Cholesterol, LDL - blood

Female

Subtilisins - metabolism

African Continental Ancestry Group - genetics

Coronary Disease - blood

European Continental Ancestry Group - genetics

Genetic Association Studies

Gene Frequency

Mice, Inbred C57BL

Linear Models

Cholesterol, HDL - genetics

Sequence Analysis, DNA

1-Alkyl-2-acetylglycerophosphocholine Esterase - metabolism

Cholesterol, LDL - genetics

Animals

Coronary Disease - genetics

Alleles

Triglycerides - blood

Cholesterol, HDL - blood

Subtilisins - genetics

Aged

Mice

Cohort Studies

Details

Title: Subtitle: Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks
Creators: Lindsay M Reynolds - Wake Forest School of Medicine, Winston-Salem, NC 27106, USA
Riccardo E Marioni - Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK; Department of Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK
Abbas Dehghan - Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3015CN, the Netherlands
Oscar H Franco - Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3015CN, the Netherlands
Aniruddh P Patel - Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; School of Medicine, Yale University, New Haven, CT 06510, USA
Yingchang Lu - The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
George Hindy - Department of Clinical Sciences in Malmö, Lund University, Clinical Research Center, Malmö 20502, Sweden
Omri Gottesman - The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Erwin P Bottinger - The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Olle Melander - Department of Clinical Sciences in Malmö, Lund University, Clinical Research Center, Malmö 20502, Sweden
Marju Orho-Melander - Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, University Hospital Malmö, Malmö 20502, Sweden
Ruth J F Loos - The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Stefano Duga - Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milano 20133, Italy
Piera Angelica Merlini - Associazione per lo Studio della Trombosi in Cardiologia (ASTC), Pavia 27100, Italy; Divisione di Cardiologia, Ospedale Niguarda, Milano 20162, Italy
Martin Farrall - Department of Cardiovascular Medicine, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
Anuj Goel - Department of Cardiovascular Medicine, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
Rosanna Asselta - Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milano 20133, Italy
Domenico Girelli - Department of Medicine, University of Verona School of Medicine, Verona 37134, Italy
Nicola Martinelli - Department of Medicine, University of Verona School of Medicine, Verona 37134, Italy
Svati H Shah - Department of Obstetrics and Gynecology, Division of Urogynecology, Duke University, Durham, NC 27710, USA; Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
Gina M Peloso - Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA
William E Kraus - Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA; Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27701, USA
Daniel J Rader - Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Alexander P Reiner - Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Epidemiology, University of Washington, Seattle, WA 98195, USA
Paul L Auer - Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA
Muredach P Reilly - Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Caroline Hayward - MRC Human Genetics, MRC IGMM, University of Edinburgh, Edinburgh EH4 2XU, UK
Ruth McPherson - Atherogenomics Laboratory, Division of Cardiology, University of Ottawa Heart Institute, Ottawa, ON K1Y 4W7, Canada
Hugh Watkins - Department of Cardiovascular Medicine, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK; Merck Sharp & Dohme Corp., Rahway, NJ 07065, USA
Joshua C Bis - Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA
Ozren Polasek - Department of Public Health, Faculty of Medicine, University of Split, Split 21000, Croatia
Diego Ardissino - Associazione per lo Studio della Trombosi in Cardiologia (ASTC), Pavia 27100, Italy; Divisione di Cardiologia, Azienda Ospedaliero-Universitaria di Parma, Parma 43100, Italy
Arend Voorman - Department of Biostatistics, University of Washington, Seattle, WA 98195, USA
Qunyuan Zhang - Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA
Judy Wang - Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA
Ian J Deary - Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK; Department of Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK
Michael Y Tsai - Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55454, USA
Alanna C Morrison - Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
Herman A Taylor - Jackson State University, Jackson, MS 39217, USA; Tougaloo College, Tougaloo, MS 39174, USA; Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA
Ingrid B Borecki - Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA
Adolfo Correa - Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA
Nathan O Stitziel - Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA
Michael E Griswold - Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA
Vilmundur Gudnason - Icelandic Heart Association, Kopavogur 201, Iceland; Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland
Leslie A Lange - Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA
Jennifer A Brody - Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA
John M Starr - Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK; Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh EH8 9JZ, UK
James G Wilson - Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA
Sumeet A Khetarpal - Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Igor Rudan - Centre for Population Health Sciences, The University of Edinburgh Medical School, Edinburgh EH8 9AG, UK; Croatian Centre for Global Health, Faculty of Medicine, University of Split, Split 21000, Croatia
Gudny Eiriksdottir - Icelandic Heart Association, Kopavogur 201, Iceland
Cornelia M van Duijn - Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3015CN, the Netherlands
Lenore J Launer - National Institute on Aging, NIH, Bethesda, MD 20892, USA
Jacy R Crosby - Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Department of Biostatistics, Bioinformatics, and Systems Biology, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA
Jose M Ordovas - Department of Cardiovascular Epidemiology and Population Genetics, National Center for Cardiovascular Investigation, Madrid 28049, Spain; IMDEA-Alimentacion, Madrid 28049, Spain; Nutrition and Genomics Laboratory, Jean Mayer-USDA Human Nutrition Research Center on Aging at Tufts University, Medford, MA 02155, USA
Charles Kooperberg - Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
Myriam Fornage - Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
Daniel Levy - National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study, Framingham, MA 01702, USA; Division of Intramural Research, NHLBI, NIH, Bethesda, MD 20892, USA
Y-D Ida Chen - Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA
Stephen S Rich - Center for Public Health Genomics and Department of Public Health Sciences, University of Virginia, Charlottesville, VA 22908, USA
Megan L Grove - Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
Aaron Isaacs - Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3015CN, the Netherlands
Paolo Zanoni - Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Bruce M Psaty - Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA; Department of Epidemiology, University of Washington, Seattle, WA 98195, USA; Group Health Research Institute, Group Health Cooperative, Seattle, WA 98101, USA; Department of Health Services, University of Washington, Seattle, WA 98195, USA
Valeska Redon - Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Johanna Jakobsdottir - Icelandic Heart Association, Kopavogur 201, Iceland
Jerome I Rotter - Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA
Serkalem Demissie - Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA; National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study, Framingham, MA 01702, USA
Kim Lawson - Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
Mary F Feitosa - Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA
Ulrike Peters - Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
Christopher J O'Donnell - Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study, Framingham, MA 01702, USA; Division of Intramural Research, NHLBI, NIH, Bethesda, MD 20892, USA; Cardiology Division, Massachusetts General Hospital, Boston, MA 02114, USA
Gail Davies - Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK; Department of Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK
Christopher Carlson - Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
Rebecca D Jackson - Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA
Kenneth Rice - Department of Biostatistics, University of Washington, Seattle, WA 98195, USA
Jennifer E Huffman - MRC Human Genetics, MRC IGMM, University of Edinburgh, Edinburgh EH4 2XU, UK
Kelli K Ryckman - Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, IA 52242, USA
Rachel H Mackey - Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA
Eric Boerwinkle - Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA
Jennifer G Robinson - Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, IA 52242, USA
Ani Manichaikul - Center for Public Health Genomics and Department of Public Health Sciences, University of Virginia, Charlottesville, VA 22908, USA
David S Siscovick - Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA; Department of Epidemiology, University of Washington, Seattle, WA 98195, USA
Sekar Kathiresan - Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Cardiology Division, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: skathiresan@partners.org
Brian Davis - Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
Pamela J Schreiner - Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN 55454, USA
Josyf C Mychaleckyj - Center for Public Health Genomics and Department of Public Health Sciences, University of Virginia, Charlottesville, VA 22908, USA
L Adrienne Cupples - Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA; National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study, Framingham, MA 01702, USA. Electronic address: adrienne@bu.edu
Kurt Lohman - Wake Forest School of Medicine, Winston-Salem, NC 27106, USA
James S Pankow - Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN 55454, USA
Albert Hofman - Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3015CN, the Netherlands
Mingyao Li - University of Pennsylvania
Aron Y Joon - Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
Andre G Uitterlinden - Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3015CN, the Netherlands
Tamara B Harris - National Institute on Aging, NIH, Bethesda, MD 20892, USA
Yongmei Liu - Wake Forest University
Kent D Taylor - Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA
Albert V Smith - Icelandic Heart Association, Kopavogur 201, Iceland; Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland
Jeanette M Stafford - Wake Forest School of Medicine, Winston-Salem, NC 27106, USA
NHLBI GO Exome Sequencing Project
Resource Type: Journal article
Publication Details: American journal of human genetics, Vol.94(2), pp.223-232
Publisher: United States
DOI: 10.1016/j.ajhg.2014.01.009
PMID: 24507774
PMCID: PMC3928662
ISSN: 1537-6605
eISSN: 1537-6605
Grant note: K08 HL114642 / NHLBI NIH HHS K08-HL114642 / NHLBI NIH HHS R01 HL120393 / NHLBI NIH HHS R01 HL107816 / NHLBI NIH HHS RC2 HL-103010 / NHLBI NIH HHS R21 HL121422 / NHLBI NIH HHS RC2 HL102923 / NHLBI NIH HHS 090532 / Wellcome Trust RC2 HL-102926 / NHLBI NIH HHS CZB/4/505 / Chief Scientist Office T32 HL007208 / NHLBI NIH HHS RC2 HL102925 / NHLBI NIH HHS UL1 TR000124 / NCATS NIH HHS RC2 HL103010 / NHLBI NIH HHS HL105756 / NHLBI NIH HHS RC2 HL-102923 / NHLBI NIH HHS R01HL107816 / NHLBI NIH HHS RC2 HL102924 / NHLBI NIH HHS U01 HG006380 / NHGRI NIH HHS RC2 HL102926 / NHLBI NIH HHS R01 HL105756 / NHLBI NIH HHS RC2 HL-102925 / NHLBI NIH HHS G0700704 / Medical Research Council ETM/55 / Chief Scientist Office MC_PC_U127561128 / Medical Research Council MR/K026992/1 / Medical Research Council BB/F019394/1 / Biotechnology and Biological Sciences Research Council RC2 HL-102924 / NHLBI NIH HHS P30 DK063491 / NIDDK NIH HHS T32HL007208 / NHLBI NIH HHS
Language: English
Date published: 02/06/2014
Academic Unit: Stead Family Department of Pediatrics; Epidemiology; Internal Medicine
Record Identifier: 9983995028602771

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